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Detangling the interrelations between MAFLD, insulin resistance, and key hormones


Metabolic dysfunction–associated fatty liver disease (MAFLD) has increasingly become a significant and highly prevalent cause of chronic liver disease, displaying a wide array of risk factors and pathophysiologic mechanisms of which only a few have so far been clearly elucidated. A bidirectional interaction between hormonal discrepancies and metabolic-related disorders, including obesity, type 2 diabetes mellitus (T2DM), and polycystic ovarian syndrome (PCOS) has been described. Since the change in nomenclature from non-alcoholic fatty liver disease (NAFLD) to MAFLD is based on the clear impact of metabolic elements on the disease, the reciprocal interactions of hormones such as insulin, adipokines (leptin and adiponectin), and estrogens have strongly pointed to the intrinsic links that lead to the heterogeneous epidemiology, clinical presentations, and risk factors involved in MAFLD in different populations. The objective of this work is twofold. Firstly, there is a brief discussion regarding the change in nomenclature as well as epidemiology, risk factors, and pathophysiologic mechanisms other than hormonal effects, which include nutrition and the gut microbiome, as well as genetic and epigenetic influences. Secondly, we review the basis of the most important hormonal factors involved in the development and progression of MAFLD that act both independently and in an interrelated manner.


Metabolic dysfunction–associated fatty liver disease (MAFLD) constitutes the most prevalent chronic liver disease in Western countries, with a pattern of increasing incidence projected to be, within only 15 years, 21% higher than that in 2018 [1, 2]. MAFLD, rather than being a single clinical entity, encompasses a disease continuum, starting from liver steatosis which can progress to steatohepatitis (previously referred to as NASH, non-alcoholic steatohepatitis), cirrhosis, and hepatocellular carcinoma depending on the initial MAFLD characteristics and presence of a wide range of predisposing factors [3]. The high prevalence of MAFLD as well as its increasing trends are intimately related to the parallel increase in obesity and type 2 diabetes mellitus (T2DM) worldwide, which, over the last few years, have been considered health epidemics [4,5,6].

Systemic metabolic derangements have been closely associated with the development and progression of MAFLD [7], with the participating role of factors such as genetic predisposition, microbiome characteristics, and hormonal factors.

The presence of MAFLD entails the development of several extrahepatic organ alterations, including chronic kidney disease, sleep apnea, colorectal cancer, and cardiovascular diseases, the latter constituting one of the main causes of mortality in patients with MAFLD [8]. The direct implication of this is that mortality in patients with MAFLD extends beyond liver complications, such as cirrhosis and hepatocellular carcinoma, and includes a multisystem impact on overall patient health which requires a multidisciplinary approach to management [1, 9,10,11].

The role of obesity, hyperinsulinemia, and T2DM, as well as the multiple hormonal background that both influences and is affected by the existence of the fatty liver spectrum, are notorious for their impact and intrinsic interrelations and will therefore be discussed. While the topics selected for analysis in this review are by no means exhaustive, they cover the broad themes of hormonal regulation of MAFLD, including the role of adipokines, estrogen, and insulin resistance (IR), identifying the latter as forming the cornerstone of liver disease. In addition, we briefly discuss the bidirectional interaction between the disease spectrum and the distinct predisposing factors, namely, dietary habits, the microbiome, and genetic and epigenetic modifications.

The assessment of liver fibrosis is essential to the evaluation of all patients with chronic liver disease in order to predict outcomes, stratify risk, and develop surveillance strategies, and evaluate response to treatment over time. Although liver biopsy remains the gold standard for assessing the stages of liver disease in cases of MAFLD, including histological assessment of fibrosis and steatohepatitis, novel methods are being developed to reduce the need for invasive procedures [12, 13]. The efficacy of liver biopsy is limited by the potential for sampling errors and suboptimal agreement among pathologists, in addition to being associated with procedural risks. Non-invasive fibrosis scores based on simple and inexpensive clinical and routine laboratory parameters, such as the NAFLD fibrosis score (NFS), the aspartate aminotransferase (AST) to platelet ratio index (APRI), and the fibrosis-4 index (FIB-4), are commonly used to identify or exclude significant or advanced fibrosis in patients with fatty liver disease. The overall accuracy of these scores has been found to be modest. Artificial intelligence (AI) is currently being integrated with conventional diagnostic methods in the hopes of performance improvement [14]. In a recent meta-analysis of 13 studies, it was shown that AI significantly improves the diagnosis of NAFLD, NASH, and liver fibrosis. In this regard, it is worthwhile mentioning the work of Katsiki et al. [13], who utilized an AI-assisted ultrasonography technique for the diagnosis of MAFLD, revealing its sensitivity to be approximately 0.97 and specificity 0.98 [15].

Transition from NAFLD to MAFLD: the revolutionizing concept

The term non-alcoholic fatty liver disease (NAFLD) was first introduced by Klatskin in 1979, while Ludwig and colleagues coined the term “non-alcoholic steatohepatitis (NASH)” in 1980 to describe fatty liver disease arising in patients with minimal or no alcohol consumption (“consumption” is defined as ≥ 30 g for men and ≥ 20 g for women) [16]. Thereafter, 40 years of research led to the advancement of our understanding of the pathophysiologic mechanisms and histologic characterization of the disease. Metabolic factors have been demonstrated as having a pivotal role in the development of fatty liver disease, not only by enhancing the onset and increasing the rate of progression to the various range of fatty liver disorders, but also by being the primary direct cause of steatosis.

In 2020, a panel of experts from 22 countries proposed a comprehensive and simple redefinition process of fatty liver disease shaped by this growing frame of knowledge. This included introducing MAFLD as a substitute for NAFLD nomenclature and laying down a set of positive criteria for diagnosis instead of criteria based on the exclusion of differential diagnoses (as NAFLD had previously been established). The criteria for MAFLD diagnosis are based on evidence of hepatic steatosis in addition to one of the following three criteria: overweight or obesity, presence of T2DM, or metabolic dysregulation [17]; similar criteria were introduced for diagnosis of MAFLD in children as well [18].

However, since the term was proposed, multiple arguments both in favor and against the new nomenclature quickly appeared, not without reason. It has been contended that a premature change in nomenclature may be counterproductive, as targeting the main risk factors still does not clarify the exact etiology of the disease given its multifactorial origin [19, 20]. However, even though some authors still believe this, a global multi-stakeholder written by experts from 135 countries joined up to lay out the reasons for which a change in nomenclature is appropriate and necessary.

Even though the change in nomenclature means that including everything that has been established in NAFLD into the term MAFLD is unwarranted, the heterogeneity of the disease makes MAFLD a term that better adjusts to the current needs for prompt diagnosis and better treatment of a greater proportion of the population who require it. Considering the central role of metabolic dysregulation in fatty liver disease development (which is taken into account in the criteria for diagnosis for MAFLD, Fig. 1), this redefinition can only lead to a better understanding of the disease as well as of the multiple features that are yet to be explained, both regarding risk factors and pathogenesis. The new definition has been accepted by numerous societies, including the Latin American Association for the Study of the Liver (ALEH) and the Asian Pacific Association for the Study of the Liver (APASL]. It has moreover recently been endorsed by a global multiple stakeholder [17, 18, 21, 22]. Notably, a robust body of evidence has confirmed the superior utility of the definition of MAFLD compared to the previous definition of NAFLD in identifying patients at high risk of fibrosis and extrahepatic complications [23,24,25].

Fig. 1
figure 1

Differences in diagnostic criteria between NAFLD and MAFLD: while the definition of NAFLD among certain groups was based on the diagnosis of absence of other causes of steatosis, MAFLD diagnosis is based on the presence of hepatic steatosis (evidenced via imaging, biochemical markers, or biopsy) plus the presence of metabolic alterations. NAFLD: non-alcoholic fatty liver disease; MAFLD: metabolic dysfunction–associated fatty liver disease; EASL: European Association for the Study of the Liver; AASLD: American Association for the Study of Liver Diseases; T2DM: type 2 diabetes mellitus

Epidemiology and risk factors

MAFLD constitutes one of the most prevalent liver diseases worldwide, just behind viral hepatitis and alcoholic liver disease (ALD) [26]. Global prevalence of MAFLD was estimated to be 25.24% in a study conducted using data from 1989 to 2015 [27]. When analyzing the tendency of increasing prevalence of fatty liver over the years, it is evident that the strong association with numerous other entities, especially obesity in more than 50% of cases, T2DM in 20%, hyperlipidemia in 70%, and hypertension and metabolic syndrome (both in 40%), determines the increased prevalence of this liver disease [27]. In broad terms, the risk factors encompass the determinants of metabolic health, such as diet and physical activity, ethnicity, age and gender, socioeconomic factors, microbiota, and alcohol consumption [28,29,30,31].


Initially, MAFLD pathogenesis was conceptualized within the popular “two-hit pathogenesis,” which could be explained in brief terms as there being an initial hit that leads to hepatic lipid accumulation due to multifactorial environmental reasons (including lifestyle, high-fat diets, obesity, and IR) and a subsequent second hit, which presents with inflammation and development of fibrosis [32].

However, with our evolving understanding of the basis of the disease, the multifactorial pathogenesis of MAFLD, referred to as the “multiple-hit pathogenesis,” was put forward by Buzzeti in 2016 [33]. These causative factors include genetic and epigenetic factors (with constantly increasing studies showing their higher than expected impact), nutritional factors, gut microbiota, metabolic health, and, finally, hormonal influence, and particularly the role of IR [34, 35]. Although each of these elements warrants an extensive discussion, the present review will be focused mainly on the hormonal factors that lead to the development and progression of MAFLD.

Genetic predisposition and epigenetic modifications

Genetic influence

The importance of genetic factors in the multiple-hit pathogenesis of MAFLD is key to our understanding. Based on the genome-wide association study carried out in 2011 [36], numerous allele variations for more than one gene were found in association with MAFLD development and disease progression. The most significant associated gene is undoubtedly PNPLA3, which encodes for adiponutrin, a protein that exerts lipolytic activity on triacylglycerides (TAGs), given its resemblance to adipose triglyceride lipase [37]. Even though normal PNPLA3 allele decreases de novo lipogenesis (DNL), increased expression of the I148M (rs738409 C/G) PNPLA3 variant was found to increase fatty acid and TAG synthesis as well as leading to impaired TAG hydrolysis, effectively increasing its hepatic levels [38]. Apart from driving lipid accumulation, this mutation drives the progression to steatohepatitis and fibrosis through a yet-to-be-elucidated mechanism. Furthermore, the PNPLA3 I148M allele has different degrees of impact on disease development as it has been found to act by sensitizing the liver to environmental stressors, which, according to recent research, may even include aspects such as air pollution [37, 39]. Based on this premise, the existence of concomitant risk factors underlying predisposing genetic mutations is what leads to MAFLD development, as is seen in the vast majority of multifactorial diseases. To a lesser degree, PNPLA3 contributes to the development of other liver diseases, including HCC, ALD, and viral hepatitis [40], which must be taken into account to more correctly predict disease outcomes. Numerous other genes have been associated with development of MAFLD and have a pivotal role in its development and progression, such as LYPLAL1 and GCKR, the latter by enhancing an increase in hepatic triacylglycerol levels and IR, respectively [41]. The rs641738 C > T variant of MBOAT7, the rs58542926 C > T allele of TM6SF2, and a large number of other genes are also involved [42,43,44,45,46]. A role for variants in the interferon lambda 3/4 (IFNλ3/4), fibronectin type III domain–containing protein 5 (FNDC5), and fibroblast growth factor 21 (FGF-21) has also been described [47,48,49,50,51]. In addition, an emerging role for other types of genetic variations such as copy number variations (CNV) has been observed [52].

Finally, researchers have noted a twofold increased risk of developing both HCC and liver cirrhosis in a cohort of hospitalized patients with T2DM [53], while several studies have shown a clear association between metabolic syndrome and HCC [54, 55].

Epigenetic reprogramming

Epigenetic modifications are changes that occur within the DNA which alter the expression of specific genes without modifying the DNA sequence [56]. Epigenetics has taken on a crucial role in describing most multifactorial diseases given the wide-ranging implications that epigenetic modifications may have in risk burden, onset, and development of disease, as well as in pathophysiology and therapeutic targets. Even though epigenetics has mostly been studied in different kinds of cancer (mainly colorectal and breast cancers) [57, 58], research into the role they play in MAFLD development has also grown rapidly.

Epigenetic modifications can be induced by diverse elements, including dietary factors, drugs, or environmental exposures. Broadly speaking, epigenetic changes can occur at any of the following three levels: direct DNA modification through methylation of CpG dinucleotides; histone modifications (acetylation or deacetylation and/or methylation or demethylation); and non-coding RNAs [59, 60].

Flexibility in gene expression in MAFLD has been attributed mainly to DNA methylation changes [59], which occur in various situations, including modulation by fructose intake in the transcriptomic mechanisms [61] as well as choline-deficiency related MAFLD [62, 63]. Moreover, development of MAFLD and steatohepatitis has been shown to be influenced by GAB2 methylation through diet and exercise [64] and METTL3 upregulation through obesity and metabolic stress [65], while differential DNA methylation patterns occur at different fibrosis stages [66]. Epigenetic marks show the phenomenon of heritability, meaning that modifications can be passed from a cell to its subsequent divisions, as well as through a non-Mendelian pattern from parents to offspring in what is known as transgenerational inheritance, which is still under study in relation to MAFLD [67, 68].

Besides DNA methylation, epigenetic mechanisms involved in MAFLD and ALD can also take place through histone acetylation and miRNAs. Histone proteins are involved in the maintenance of chromatin structure and gene expression, while acetylation causes activation of gene transcription and deacetylation causes gene repression. Aberrant histone modifications promote the development of IR and DM2 [69].

The effect of circRNAs on MAFLD pathogenesis stems from the fact that IR and abnormal lipid metabolism are the hallmarks of the disease. By inducing mitochondrial dysfunction with a generation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress, as well as modulating lipophagy in steatotic livers, circRNAs play a role in the development of the conditions that predispose to MAFLD. A few examples of circRNAs involved in MAFLD pathogenesis include the following: circScd1, which increases hepatocellular lipidosis via the JAK2/STAT5 pathway; circRNA_002581, which promotes steatohepatitis development through dysregulation of autophagy; and circRNA_0049392, by regulating low-density lipoprotein (LDL) levels in serum [70].

Similarly, the beneficial role of SIRT1, which in fact has led to new therapeutic targets, cannot be overlooked. Sirtuins are members of the silent information regulator 2 (Sir2) family, a group of class III highly conserved NAD + -dependent histone and protein deacetylases playing a pivotal role in numerous biological processes. There are seven different sirtuins in mammals (SIRT1-7), of which SIRT1 is the most recognized regulator involved in MAFLD, with both nuclear and cytoplasmic locations [71, 72]. SIRT1 is a key metabolic regulator which maintains homeostasis by regulating the transcriptional activity of multiple factors. The two principal contributions of SIRT1 in fatty liver disease are lipid metabolism and insulin secretion, along with concomitant regulation of oxidative stress and liver inflammation. Regarding lipid metabolism, SIRT1 causes downregulation of SREBP-1c’s transcriptional activity by deacetylating lysine in its DNA-binding domain [73], as well as inducing histone deacetylation in the ChREBP gene [74]. It thereby suppresses downstream lipogenic enzyme gene expression, consisting of enzymes such as fatty acid synthase (FAS), acetyl-CoA carboxylase 1 (ACC1), stearoyl-CoA desaturase-1 (SCD1), and elongase of the long-chain fatty acid family 6 (ELOVL6), which participate in the synthesis of free fatty acid (FFA) and TAG in the liver [72]. Furthermore, by increasing PPARα-dependent fatty acid β-oxidation (by deacetylating PGC-1α), SIRT1 increases hepatic lipid utilization, alleviating fatty liver. It has been shown that SIRT1 activation increases lipolysis by repressing PPARγ in adipose tissue, thereby inhibiting adipogenesis. Moreover, by regulating PPARγ and FOXO1, this sirtuin also modulates the secretion of insulin-sensitizing factors, such as adiponectin and FGF21 [75].

Due to its insulin regulating mechanism, which is known to constitute the basis for MAFLD genesis, SIRT1 improves the insulin sensitivity of liver, skeletal muscle, and adipose tissue, increases insulin secretion [through inhibition of uncoupling protein-2 (UCP-2)] [76], and conserves pancreatic β-cell mass [77].

Given these central functions in the pathogenesis of fatty liver disease, SIRT1 has been the target of a number of therapeutic drugs, including resveratrol, SRT1720, and NAD + precursors (nicotinamide riboside, nicotinic acid, and nicotinamide mononucleotide) which activate SIRT1, enhancing its functions and reducing overall oxidative stress [72].

Finally, a serum microRNA (miRNA) profile revealed the potential relationship between different miRNAs and the presence of steatosis or steatohepatitis in 16 patients. It was reported that miR-374a-5p, miR-1-3p, and miR-23a-3p do not target genes that are directly involved in the pathogenesis of MAFLD [78]. On the other hand, the specific roles of some miRNAs are still unknown. An example of this is miR-192-5p, which was originally found to have a beneficial role in MAFLD development. This observation is based on miR-192-5p downregulation seen in high-fat diet-induced MAFLD in mice, as well as the inhibitory lipid synthesis function found when upregulated (by SCD1 targeting) [79]. However, it was later determined that lipotoxic hepatocytes secreting miR-192-5p contribute to M1 macrophage activation, inflammatory response, and development of hepatic steatosis in MAFLD [80, 81]. One final example is miR-423-5p, which is upregulated in individuals with metabolic healthy obesity (MHO) compared to metabolic abnormal obesity (MAO), and appears to be associated with downregulation of proinflammatory markers that are linked to IR [82]. It has been considered a therapeutic target, given that its inhibition of the L/R-type pyruvate kinase (PKLR) could lead to a decrease in de novo lipogenesis (DNL) and oxidative phosphorylation in mitochondria, having a positive effect in the early stages of MAFLD. However, this particular miRNA was also found to inhibit the AMPK complex, thus contributing to progression to steatohepatitis as well as suppressing tumor necrosis factor (TNF) and Fas cell surface death receptor (FAS), possibly contributing to fibrosis and establishment of HCC [78].

Nutritional factors and gut microbiota

Microbiome and MAFLD

Human gut microbiota plays a pivotal role in the development of MAFLD through what is known as the gut-liver (or liver-microbiome) axis [83, 84]. Undoubtedly, the microbiome constitutes an important regulator of health and disease states in living organisms, dubbed the “second genome” [85]. One of the first studies demonstrating the influence of the microbiome on MAFLD was carried out in 2003 through the use of VSL#3 probiotics (as well as anti-TNF antibodies), which showed improvement in histological features of MAFLD in ob/ob mice [86]. Since then, multiple studies have shown the interplay between these two factors, starting from identification of what is referred to as the obesity-associated gut microbiome, a transmissible “enterotype” capable of increasing total body fat [87].

The gut-liver axis refers to the bidirectional relationship between the liver and the gut microbiome. This feedback loop is established by both the transport of gut-derived products to the liver as well as the secretion of bile and hepatic antibodies into the intestine [88]. Bile acids (BAs) are not only important for the absorption of lipid-soluble nutrients in the intestine but also crucial messengers that impact the gut microbiome and metabolic homeostasis. As important signaling molecules are involved in lipid and glucose metabolism, dysregulation of BA homeostasis has been associated with MAFLD disease severity [89]. However, the data published in the literature on the relationship between IR and the influence of bile acid on the disease are inconsistent. A 2021 study found that steatosis-associated increase of total cholic acid in plasma depends on the degree of systemic IR (assessed by HOMA2) [90], while another study found that MAFLD is associated with significant changes in bile acid composition, hypothesized to be unaffected by T2DM, and correlated with the histological features of steatohepatitis [91].

An important breakthrough occurred when obesity and the gut microbiome were discovered to be independent risk factors for the development of MAFLD through a study in which germ-free mice were colonized with different microbiota from two different C57BL/6 J mice that responded differently to high-fat diets (HFD): it was found that the mice that received the microbiome from MAFLD mice developed both hyperinsulinemia and macrovesicular steatosis (along with increased expression of genes involved in DNL), independent of the presence of obesity [92]. Following on this, Alferink et al. [93] carried out the largest scale population-based study (consisting of 1355 adults) which shed light on the association between specific gut microbiome characteristics and MAFLD: it determined that low-diversity microbiomes and the presence of Coprococcus and Ruminococcus gnavus were associated with liver steatosis [93]. Dysbiosis may lead to a cascade of mechanisms that modify the epithelial properties and facilitate bacterial translocation in diseases such as T2DM, obesity, and MAFLD [94]. Furthermore, endogenous alcohol production by steatosis-associated intestinal microbiota, its increased serum levels, and, consequently, its well-established role in inflammation induced by oxidative stress laid the basis for understanding the histological similarities between ALD and MAFLD [95, 96]. Recently, a role for microbiota in the pathogenesis of MAFLD in lean subjects has been described [97].

There is an important link not only between epigenetic modifiers and MAFLD, but also between epiphenomena and the other factors contributing to MAFLD development. Microbiome alteration through environmental and dietary factors is not the exception.

Dietary changes can induce gut microbiome change, this being confirmed through the finding that consumption of > 7.5 g/day of insoluble fiber improved liver fibrosis according to three different fibrosis evaluating scores [98].

There is a pivotal association in MAFLD development involving the microbiome and estrogen production. Basically, increased endogenous estrogen circulation occurs for the two following reasons: firstly, deconjugation of conjugated estrogen metabolites marked for excretion, which pushes them back through the enterohepatic circulation; and, secondly, the breakdown of otherwise indigestible dietary polyphenols to synthesize estrogen-mimicking compounds [85]. The relationship between estrogens and MAFLD will be discussed in the following sections.

Nutritional influence

A wide range of dietary factors also plays an important role in the development of MAFLD either by altering hepatic metabolism directly or by promoting dysbiosis [54, 58]. Excessive calorie intake is a major risk factor for MAFLD as well as for the entities directly related to fatty liver development (e.g., obesity and T2DM). While high-fat diets induce endotoxemia and low-grade systemic inflammation, trans-fat consumption stimulates cholesterogenesis, establishing a risk factor not only for MAFLD but also for the development of steatohepatitis [99,100,101]. Fructose, on the other hand, has been extensively studied for its role in MAFLD development by stimulating DNL and gluconeogenesis, which in turn stimulate ChREBP and SREBP1c, along with the induction of IR and mitochondrial oxidative stress [102, 103].

Mitochondrial dysfunction and oxidative stress

Alterations in mitochondrial structure and function, which constitute a determinant factor in MAFLD pathogenesis, include mitochondrial DNA depletion, morphological abnormalities, and changes in the respiratory chain, as well as β-oxidation [33]. There is strong evidence showing that respiratory chain deficiency in mitochondrial dysfunction plays a key role in steatohepatitis and also that alterations in mitochondrial β-oxidation of FFAs generate ROS. Oxidative stress acts on a fat-rich environment by inducing lipid peroxidation, which releases highly reactive substances (aldehyde derivatives) leading to deleterious effects on hepatocytes [129]. The above-described actions lead to mitochondrial dysfunction, which consequently drives the production of even more ROS, leading to a vicious cycle which eventually results in inflammation and apoptosis. Additionally, cytokine generation (specifically of TNF-α, TGF-β, and FAS ligand) by ROS and the products of lipid peroxidation play a key role in the development of steatohepatitis and fibrosis [129].

Finally, it is essential to understand how adipokines might also induce oxidative stress. Leptin is arguably the main adipokine mediator in the MAFLD pathogenic spectrum, as discussed in greater detail in the following sections. This segment, however, deals with the significant contribution of leptin to the oxidative stress–mediated damage in MAFLD. Leptin interacts with a variety of cells in the liver, including macrophages. Research has revealed that leptin acts on these cells in steatotic livers, prompting peroxynitrite-mediated oxidative stress, which is comprised of three main actions, namely, leptin-mediated protein radical formation, tyrosine nitration, and activation of Kupffer cells [130]. Thus, by promoting further oxidative stress, leptin probably plays an important role in the development of steatohepatitis.

Hormonal factors and IR

Glucose transport and hyperinsulinemia

Hyperinsulinemia is closely related to a wide range of components of metabolic dysfunction. Once thought to be a consequence of metabolic dysfunction (as in the case of obesity), recent evidence has indicated that hyperinsulinemia might well be the cause of metabolic abnormalities due to its role in inflammatory and multisystem pathways [104,105,106,107] (Fig. 2).

Fig. 2
figure 2

Hepatic fat metabolism’s direct relationship with IR and MAFLD: FFAs from the diet or as a product of lipolysis are stored in the liver as triglycerides, which constitute the main storage form of fat in this organ. Increased hepatic TAG levels contribute to the development of IR, which directly contributes to MAFLD development through the downregulation of IRS-2 and inhibition of β- oxidation of FFAs, which in turn inhibit lipolysis and stimulate PI3K, all of these leading to the overexpression of SREBP-1c and thus increase DNL and consequently hepatic steatosis. On the other hand, insulin directly increases nuclear translocation of PI3K, which modulates the cellular response to ER stress, leading to UPR (unfolded protein response) and therefore the activation of JNK, an activator of apoptosis and inflammation, resulting in steatosis and steatohepatitis. Additionally, JNK activation leads to impaired insulin signaling. FFAs: free fatty acids; CoA: coenzymeA; TAG: triacyglycerol; MAFLD: metabolic dysfunction–associated fatty liver disease; DGAT2: diacylglycerol O-acyltransferase 2; IRS-2: insulin receptor substrate 2; PI3K: phosphatidylinositol-3 kinase; SREBP-1c: sterol response element–binding protein 1c; DNL: de novo lipogenesis; XBP-1: X-box-binding protein 1; ER: eEndoplasmic reticulum; UPR: unfolded protein response; JNK: c-Jun kinase

IR is the result of multiple abnormalities that start at a cellular level, involving abnormalities in intracellular signaling pathways and, in the case of peripheral IR, alterations in glucose transporters [108]. Glucose transporter-4 (GLUT-4) is the main protein implicated in glucose transport in cells for its catabolism. Multiple parameters in the body are closely regulated for optimal homeostasis, these including such variables as pH, electrolyte concentrations, and glucose. Serum glucose levels are tightly regulated through multiple mechanisms, including peripheral and central nervous system control and hormonal influence involving glucagon, insulin, amylin, and GLP-1 (glucagon-like peptide-1) [109]. Serum glucose levels must be maintained within a specific range to prevent altered states of consciousness due to hypoglycemia or peripheral toxicity owing to chronic hyperglycemic states. After carbohydrate ingestion, the major cellular mechanism that diminishes blood glucose levels is insulin-stimulated glucose transport into skeletal muscle, which can both store it as glycogen and oxidize it for the subsequent metabolic steps, as described below. The principal glucose transporter protein that mediates skeletal muscle uptake is GLUT4, which plays a key role in body glucose homeostasis [110]. However, several GLUT subtypes play important roles in carbohydrate transport in different organs, leading to a certain degree of specificity.

GLUT-4 in the liver is principally expressed in hepatocytes and in endothelial and hepatic stellate cells (HSC) [111]. Expression in HSC is promoted by leptin signaling, leading to its activation and consequent contribution to fibrogenesis in MAFLD. It has been reported that GLP-1R agonists increase lipolysis, reduce lipogenesis, and improve hepatic fibrosis. Exendin-4 (a GLP agonist) was shown to improve hepatic steatosis by enhancing GLUT-4 via GLP-1R, as well as improving fibrosis by inhibiting connective tissue growth factor expression in HSC, thus exerting a protective effect on the liver in patients with T2DM and obesity [112].

Persistent hyperglycemia leads to a condition known as glucotoxicity, characterized by decreased insulin secretion from pancreatic β-cells and an increase in IR [113]. This well-known condition, which induces IR, affects both hepatic and adipose tissue metabolism, playing a crucial role in MAFLD pathogenesis. The key event is the suppression of hormone-sensitive lipase in adipocytes by IR, which increases lipolysis and thus FFA flow from adipose tissue to the liver. Persistently elevated glucose and hyperinsulinemia stimulate hepatic DNL by upregulating hepatic lipogenic transcription factors such as SREBP-1c and ChREBP, which enhance the activities of glucokinase, fatty acid synthase, and acetyl-CoA carboxylase [114]. Thus, while IR promotes FFA accumulation in the liver, the latter causes hepatic IR characterized by a lack of suppression of endogenous glucose production in the liver [115].

Lipid metabolism and IR

MAFLD is clinically characterized by the existence of visible fat-containing lipid droplets in 5% of hepatocytes, the latter determined when thin sections are assessed by light microscopy or by detection of excess of a percentage threshold of 5.56% when evaluated through proton magnetic resonance spectroscopy [116]. Hepatic steatosis is associated with IR in the liver, adipose tissue, and skeletal muscle, independent of the level of adiposity [117]. Moreover, exceeding a specific threshold for hepatic fat accumulation (1.5% for liver IR and 6% for muscle IR) is counterintuitively not associated with increased IR. Having said this, hepatic DNL was found to be inversely correlated with hepatic and peripheral insulin sensitivity, but directly correlated with plasma glucose and insulin concentrations. Along with weight loss, there are also decreased plasma glucose levels, insulin concentrations, and intrahepatic TAG content [118].

Triglycerides are the storage form of fat in the MAFLD liver, produced by the esterification of glycerol with three FFAs [119]. FFAs can originate from diet (exogenously) or endogenously through lipolysis in adipose tissue or from DNL in the liver. A series of steps then follows that leads directly to the development of IR (see Fig. 2) [33, 119]. Even though TAG accumulation is not hepatotoxic per se and can even act as a defensive mechanism to balance FFA excess, inhibition of DGAT2 expression results in a reduction of intrahepatic TAGs and subsequent increase of FFA oxidation, leading to a worsening of steatohepatitis and increased portal hypertension [120].

Thus, increased TAG concentration is an epiphenomenon which happens simultaneously with toxic metabolite generation, lipotoxicity, and liver damage [33]. Through quantitative proteomics, it has been shown that liver steatosis alters hepatokine secretion and that these protein signals alter fatty acid metabolism and induce inflammation and IR in other cell types [116].

Uric acid and MAFLD

Hyperuricemia has recently been associated with metabolic syndrome, IR, and oxidative stress–related conditions. As mentioned above, the relationship between IR and MAFLD development suggests that there is an indirect association between uric acid (UA) levels and MAFLD. Based on this hypothesis, two recent studies were conducted in the Korean population which showed that serum UA concentrations are associated with the degree of hepatic steatosis, this being found to be an independent risk factor for incidental fatty liver in a healthy population, with an adjusted hazard ratio reaching up to 1.51 [121, 122]. IR might act as the link between hyperuricemia and components of the metabolic syndrome, such as hypertension and dyslipidemia [123].

Systemic low-grade chronic inflammation and oxidative stress contribute to the physiopathology of fatty liver, this shedding light on the as yet only partially elucidated function of UA in MAFLD. A possible pathway that could account for the increased steatosis in patients with high UA levels is the observed direct hepatic lipogenic effect exerted through mitochondrial oxidative stress: the latter acts synergically with fructose-induced TAG production, with increased UA leading to increased hepatic response to fructose-induced lipogenesis, increasing UA even further, resulting in a vicious cycle [124]. Additionally, fatty liver predisposition to steatosis is linked to metabolism of fructose by fructokinase C, resulting in the consumption of ATP, nucleotide turnover, and UA generation, which mediates fat accumulation [125]. Furthermore, differential glucose transporter 9 (GLUT-9), which mediates UA uptake into hepatocytes, might play an important role in UA-induced MAFLD [126]. A meta-analysis carried out by Darmawan et al. [127] showed a significant association between serum UA levels and the presence of MAFLD, with an adjusted OR of 1.92. Furthermore, within this analysis, two studies revealed a correlation between serum UA and the severity of liver disease. Another analysis published in the same year also showed a positive correlation between UA and MAFLD, this time with a pooled OR of 2.08 [128].


Adipose tissue is now recognized not only as the main site of storage of excess energy derived from food intake but also as an endocrine organ [131]. This highly dynamic organ, along with the liver which is arguably the body’s main metabolic regulator, regulates body homeostasis through the release of a number of bioactive substances known as adipokines, which have been identified as a crucial signaling mechanism in MAFLD development and progression [132]. By triggering chronic low-grade inflammation, modulating metabolism, and inducing pleiotropic effects, adipokines have a central role not only in the genesis of MAFLD, but also in other obesity-related digestive diseases (e.g., cholelithiasis, Barret’s esophagus, and esophageal and colorectal cancer) as well as pancreatic cancer and diabetes [131]. The two main adipokines are leptin and adiponectin (Fig. 3).

Fig. 3
figure 3

Overview of hormonal factor in MAFLD: in patients with MAFLD, leptin levels increase, leading to the activation of different pathways, which ultimately results in the activation of stellate cells and secretion of extracellular matrix, leading to fibrosis. Hyper-responsiveness to leptin-mediated signaling leads to increased expression of CD14 and increased progression to steatohepatitis. Decreased levels of adiponectin, on the other hand, decrease its protective effects, namely, antifibrotic, anti-inflammatory, and antioxidant. MAFLD: metabolic dysfunction–associated fatty liver disease; TGF-β1: transforming growth factor beta; mTOR: mammalian target of rapamycin; AdipoR1: adipocyte receptor-1; AMPK: AMP-activated protein kinase; ECM: extracellular matrix; TNF-α: tumor necrosis factor alpha; IL-6: interleukin 6; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells


Leptin, the first adipokine identified, is a hormone principally expressed in adipose tissue; it displays pleiotropic effects involving neuroendocrine regulation, energy homeostasis, and even angiogenesis, as well as cognition and immune function [133]. It is widely known as the “satiety hormone,” playing a major role in the pathogenesis of obesity [134].

Leptin’s role in MAFLD pathogenesis is dual and involves a variety of mechanisms, this being supported by the fact that a high percentage of patients with MAFLD have increased weight or obesity. It is well known that leptin secretion is proportional to the increase in body fat volume, it being a mechanism that curbs the appetite in order to modulate energy balance and weight. However, after a certain limit, increased leptin secretion no longer exerts its expected effect, and leptin resistance ensues. Therefore, it is important to establish the fact that most patients with MAFLD also have hyperleptinemia, while a minority might present with hypo- or normoleptinemia.

In hepatocytes, leptin acts primarily via the JAK2/STAT3 pathway, while it can also act through the PIK3/Akt/mTOR pathway, particularly in insulin sensitivity improvement. Increased leptin exerts a proinflammatory effect and, by regulating cytokine production and T cell activation, increases susceptibility to hepatotoxic events. A correlation has been found between increased circulating leptin levels and MAFLD severity [134, 135]. There is an important overlap between hepatic insulin and leptin signaling pathways, which points to the intrinsic interrelation between seemingly separate hormonal factors. In this regard, Duan et al. [136] found that the src homology 2 domain–containing adapter protein B (SH2)-B mediated leptin-stimulated phosphorylation of IRS proteins, resulting in activation of the PIK3 pathway, which might be involved in MAFLD pathogenesis.

Leptin has a double role in progression of fatty liver disease. Although it has been reported that it may counteract the mechanisms leading to hepatic steatosis in the early stages of MAFLD (i.e., until leptin resistance develops), its role in inflammation and fibrogenesis is adverse. In hepatic cells, leptin inhibits DNL and stimulates FFA oxidation, reducing hepatic lipid content and thus inducing lipotoxicosis and lipoapoptosis [137]. Furthermore, leptin decreases hepatic glucose production by reducing glycogenolysis, its role in gluconeogenesis at present being controversial, and also suppresses hepatic glucogenesis, thus creating an insulin-sensitizing environment and reducing glucotoxicity [138].

On the other hand, after reaching a threshold for IR and steatosis, leptin acts as a proinflammatory and profibrogenic adipokine, as it upregulates collagen α1 and increases HSCs’ activation, which express leptin receptors (LepRb) [139]. Activated HSCs also produce leptin, which fuels the vicious cycle by further inducing HSC proliferation and inhibiting apoptosis, leading to liver fibrosis [140]. LepRb can also be found in Kupffer and sinusoidal endothelial cells, through which leptin signals the upregulation of matrix remodeling enzymes including TGF-β1 [141]. Furthermore, it also upregulates CD14 expression in Kupffer cells. CD14 is an endotoxin bacterial lipopolysaccharide receptor, upregulation of which leads to increased sensitizing of the cells to harmful stimuli and, consequently, greater oxidative stress. Upregulation of CD14 was found to increase the development of steatohepatitis and fibrosis, even in the absence of previous steatosis [114, 142] (Fig. 3). The absolute requirement of leptin for hepatic fibrosis was confirmed in a study carried out by Leclercq and colleagues [143].

Lipodystrophic syndromes (LS), which can be either generalized or partial, are disorders in which there is absence of subcutaneous fat and have been associated with HIV therapy (HAART) as well as other causes, such as genetic mutations (non-HAART LS) [144]. LS often lead to metabolic defects due to changes in the levels of circulating adipokines. These include IR, T2DM, and hypertriglyceridemia, which may lead to the development of atherosclerosis, acute pancreatitis, and MAFLD. Leptin replacement therapy (LRT) with metreleptin has been found to have a positive effect on the group of LS that present with either normal or low serum leptin levels, showing improvement in laboratory values in lipid and hepatic profiles as well as in fasting plasma glucose and Hb1Ac levels, irrespective of food intake, body weight, and insulin levels [145, 146]. However, it is possible that a minority of patients with MAFLD who present with hypoleptinemia could potentially benefit from treatment with LRT. [147]


Adiponectin is an adipokine that improves hepatic and peripheral IR and has hepatoprotective and anti-inflammatory activities through the deactivation of nuclear factor Κb (NF-Κb), by stimulating the secretion of anti-inflammatory cytokines, including interleukin-10 (IL-10) and IL-1 receptor antagonist. It also suppresses the release of proinflammatory cytokines such as TNF-α, IL-6, and interferon-γ (IFN-γ). Adiponectin is involved in the AMP-activated protein kinase (AMPK) and PPARα pathway and acts through receptors AdipoR1 and AdipoR2 [148]. Adiponectin is diminished in conditions such as visceral obesity and IR and has differential expression in the different stages leading from simple steatosis to steatohepatitis. A 2004 study showed that 77% of patients with steatohepatitis presented adiponectin levels of less than 10 μg/mL and HOMA-IR greater than 3 units, while only 33% of those with simple steatosis had these findings [149].

Interestingly, the genetic factor also plays an important role in adiponectin’s role in MAFLD pathogenesis; a 4-year follow-up survey suggesting increased MAFLD progression with three specific single nucleotide polymorphisms (SNPs) in the adiponectin gene (rs2241767, rs1501299, rs3774261) [150]. A systematic review and meta-analysis showed relative hypoadiponectinemia in patients with MAFLD when compared with controls, with a WMD of 3.00 (simple steatosis)–4.75 (steatohepatitis). Furthermore, there were also differences in adiponectin levels between steatosis and steatohepatitis patients, with lower adiponectin levels in patients with steatohepatitis (WMD 1.81) [151].


Several factors account for the differences in the incidence and progression of inflammatory metabolic diseases among females and males, MAFLD not being an exception. Among these factors, estrogens play a central role, mainly through the regulation of several metabolic and inflammatory pathways [152] (Fig. 4). A number of studies started to shed light on these characteristics by studying its influence on the cardiovascular system, demonstrating an increased risk in postmenopausal women [153]. Similar studies conducted by Gutierrez-Gröbe et al. [154] showed an increased incidence of MAFLD in postmenopausal women and an even higher incidence in patients with polycystic ovarian syndrome (PCOS). By acting through the estrogen receptors (ER) ERα, ERβ, and GPER (G-protein coupled estrogen receptor), estrogens limit dietary-induced DNL, favor the distribution of adipose tissue to subcutaneous deposits, and reduce FFA uptake, thus restricting the influx of these into the liver [152].

Fig. 4
figure 4

Effects of estrogen on prevention of MAFLD. Estrogen exerts a protective effect by decreasing overall FFA influx into the liver as well as by decreasing de novo lipogenesis and promoting β-oxidation of FFA thereby acting against persistent activation of alternative pathways of FFA oxidation, which leads to the generation of reactive oxygen species and, finally, to inflammatory response, contributing to the progression to steatohepatitis. ERα: estrogen receptor-α; ERβ: estrogen receptor-β; GPER: G-protein-coupled estrogen receptor-1; FFA: free fatty acid; DNL: de novo lipogenesis; ROS: reactive oxygen species

Multiple studies have been conducted in rats that point to the role of estrogens in fatty liver genesis. D’eon et al. [155] found that estrogen supplementation in ovariectomized rats decreases the hepatic expression of SREBP-1c, decreasing lipogenic enzyme synthesis. Furthermore, an estrogen-deficient state in rats is seen to directly lead to hepatic steatosis [156]. In a clinical trial including more than 5000 women, tamoxifen (an estrogen receptor antagonist) was found to increase the incidence of fatty liver in overweight and obese women [157].

Regarding a topic touched upon briefly above, the microbiome regulates steroid hormone metabolism by encoding enzymes that have the capability of deconjugating already conjugated estrogen metabolites, increasing the active form in circulation. Additionally, dietary polyphenols can be broken down by the microbiota giving rise to estrogen-like compounds that exert estrogen’s hormonal effects to different degrees [85]. Even though the direct relationship between microbiome, estrogen availability, and MAFLD has not to date been directly decoded, the indirect relationships between these three variables make the association extremely likely.

Conclusions and outlook

The data summarized in this review outline the role of the “multiple parallel hits” involved in MAFLD, highlighting their connection and the importance of the hormonal component. The role of hormones in the onset and progression of MAFLD is only a tiny part of the wide spectrum of factors involved in this metabolic disease, as well as the complex interrelations that are yet to be discovered. That said, its importance is indisputable and could be considered the basis for its direct implications in development of steatosis and progression to steatohepatitis. The core of hormonal influence on MAFLD is undoubtedly centered on IR, which by itself carries a complete set of different risk factors, genetic components, and pathophysiologic processes. Beyond this, IR starts a chain reaction involving a wide range of processes, including alteration in de novo lipogenesis, fatty acid oxidation, and activation of second messenger systems, as well as generation of reactive oxygen species and subsequent inflammation. Adipokines are central to the understanding MAFLD not only by virtue of their involvement in overweight and obesity, but also through their direct impact on hepatic metabolism and their endocrine effect on stellate cells. Estrogen has time after time shown its effect on a variety of diseases that present sexual dimorphism, including MAFLD. In this context, greater insight into the hormonal mechanisms underlying MAFLD and their role in risk factor burden will likely provide a solid basis for fully recognizing MAFLD to be a multidisciplinary disease.



Metabolic dysfunction–associated fatty liver disease


Type 2 diabetes mellitus


Polycystic ovarian syndrome


Non-alcoholic fatty liver disease


Non-alcoholic steatohepatitis


Latin American Association for the Study of the Liver




Hepatocellular carcinoma


Alcoholic liver disease


Deoxyribonucleic acid


Ribonucleic acid


GRB2-associated-binding protein 2


Growth factor receptor–bound protein 2


Methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit


Tumor necrosis factor




De novo lipogenesis


Carbohydrate response element–binding protein


Sterol response element–binding protein 1c


Glucose transporter (derivatives: GLUT-4, GLUT-9)


Potential of hydrogen


Glucagon-like peptide-1


Hepatic stellate cell


Glucagon-like peptide-1 receptor


Free fatty acid


Diacylglycerol O-Acyltransferase 2


Uric acid


Adenosine triphosphate


Peroxisome proliferator–activated receptor-alpha


Nuclear factor kappa-light-chain-enhancer of activated B cells


Insulin resistance






AMP-activated protein kinase

AdipoR1, 2:

Adiponectin receptor-1, 2


Homeostatic model assessment of insulin resistance


Single nucleotide polymorphism


Estrogen receptor


G-protein-coupled estrogen receptor


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SCP: manuscript writing, data analysis, and critical revision; ME: planning and critical revision; NM-S: conceptualization, manuscript design, critical revision, supervision.

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Pal, S.C., Eslam, M. & Mendez-Sanchez, N. Detangling the interrelations between MAFLD, insulin resistance, and key hormones. Hormones (2022).

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  • Insulin resistance
  • Adipokines
  • Estrogen