Signalling mechanisms linking hepatic glucose and lipid metabolism
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Fatty liver and hepatic triglyceride accumulation are strongly associated with obesity, insulin resistance and type 2 diabetes, and are subject to nutritional influences. Hepatic regulation of glucose and lipid homeostasis is influenced by a complex system of hormones, hormonally regulated signalling pathways and transcription factors. Recently, considerable progress has been made in elucidating molecular pathways and potential factors that are affected in insulin-resistant states. In this review we discuss some of the key factors that are involved in both the regulation of glucose and lipid metabolism in the liver. Understanding the molecular network that links hepatic lipid accumulation and impaired glucose metabolism may provide targets for dietary or pharmacological interventions.
KeywordsFatty liver Hepatic glucose and lipid homeostasis Insulin resistance Signalling Transcription factors
AMP-activated protein kinase
carnitine palmitoyl transferase-1
carbohydrate response element-binding protein
fatty acid synthase
forkhead transcription factor
11β-hydroxysteroid dehydrogenase 1 (encoded by the gene HSD11B1)
liver pyruvate kinase
liver X receptor
PPARγ coactivator 1α
protein kinase B/Akt
peroxisome proliferator-activated receptor
polyunsaturated fatty acids
retinoid X receptor
sterol response element-binding protein
Role of the liver in glucose metabolism
In the liver, insulin regulates fasting glucose concentrations by inhibiting hepatic glucose production and stimulating glycogen synthesis. Hepatic glucose production involves two different mechanisms: glycogenolysis and gluconeogenesis. Glycogenolysis produces glucose during a relatively short-term fast of up to several hours, and is suppressed by insulin within 1–2 h after food intake in healthy subjects . During longer periods of fasting (>12–14 h), liver glycogen stores become depleted and there is an increase in the percentage contribution made by gluconeogenesis to the total glucose supply . This involves the de novo synthesis of glucose from precursors such as pyruvate, lactate and glycerol and glucogenic amino acids. Increased gluconeogenesis also occurs in other states involving low insulin concentration (e.g. type 1 diabetes, secondary types of diabetes), and in states of relative insulin deficiency where the liver is insulin resistant (e.g. obesity, type 2 diabetes). Notably, in diabetic states, the absolute amount of hepatic glucose production is only moderately increased relative to that in healthy controls, but is inadequately suppressed relative to the raised concentrations of insulin and glucose .
Role of the liver in lipid metabolism
Consistent with its function as an anabolic hormone, insulin promotes the synthesis, and inhibits the degradation of lipids. Insulin-regulated lipid homeostasis is modulated by sterol response element-binding proteins (SREBPs) that activate the expression of over 30 genes involved in the synthesis and uptake of fatty acids, triglycerides, cholesterol and phospholipids . High glucose and insulin have also been shown to inhibit fatty acid oxidation . When delivered to the liver in large quantities, glucose is first converted to glycogen and stored. Once glycogen stores are replenished, glucose enters the glycolysis pathway and thereby provides carbons for de novo lipogenesis. Lipids are then stored as triglycerides or exported from the liver as VLDL.
Acute vs prolonged exposure to insulin
Insulin is commonly viewed as a positive regulator of fatty acid synthesis, as it promotes the expression of FASN and ACAC. However, when acutely elevated, insulin can reduce liver fat accumulation in normoinsulinaemic mice . Following insulin-induced phosphorylation of the insulin receptor and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), the proteins are internalised and interact with FASN, reducing its catalytic activity. This is not observed in hyperinsulinaemic mice, indicating that the acute effects of insulin on FASN activity are dependent upon the prior insulinaemic state.
Alternatively, chronic hyperinsulinaemia may be linked to hepatic fat accumulation by forkhead transcription factors . Insulin is known to activate insulin receptor substrates IRS1 and IRS2, via phosphorylation by Akt and consequent inhibition of forkhead transcription factors (FOXO1 and FOXA2). FOXO1 is regulated via the IRS2 pathway, shutting down hepatic gluconeogenesis. FOXA2, which inhibits hepatic fatty-acid-oxidation when phosphorylated, can be induced both over the IRS2 and the IRS1 pathways, which may result in increased insulin sensitivity of FOXA2 compared with FOXO1. Therefore, in states of reduced insulin sensitivity, insulin fails to inhibit glucose production, which in turn increases insulin secretion and enhances hyperinsulinaemia. On the other hand, because of the increased sensitivity of the pathway shutting down fatty acid oxidation, triglycerides may accumulate in the liver, leading to hepatic steatosis in the longer term.
Liver X receptor α
Liver X receptors (LXRs) are members of the nuclear receptor family, and are now recognised as important regulators of cholesterol metabolism, lipid biosynthesis and glucose homeostasis . LXRs are also involved in regulating the storage and oxidation of dietary fat . Two isoforms have been described, LXRα and LXRβ. The beta isoform is ubiquitously expressed and has recently been implicated in adipocyte growth, glucose homeostasis and beta cell function .
Peroxisome proliferator-activated receptor α
PPARs are ligand-activated transcription factors that play an important role in adipocyte differentiation and fatty acid catabolism. Three subtypes (α, δ [also known as β], γ) have been identified and show tissue-specific expression . PPARγ is only expressed at very low levels in the healthy liver, but levels are markedly increased in rodents with fatty liver and insulin resistance . To date, it is unknown whether this phenomenon also exists in humans. PPARδ is ubiquitously expressed and is currently the least well understood of the PPAR subtypes. It has been shown to modulate the inflammatory status of foam cells in atherosclerotic lesions and to be involved in muscle lipid metabolism in mice [53, 54].
PPARα, the predominantly expressed form in the liver [55, 56], is involved in promoting gluconeogenesis [57, 58] and stimulates the transcription of genes that are critical for peroxisomal and mitochondrial oxidation of fatty acids . By modulating gene expression, PPARα stimulates hepatic fatty acid oxidation to supply substrates that can be metabolised by other tissues. Supporting evidence is provided by the finding that PPARα-null mice exposed to prolonged fasting develop fatty liver and hypoglycaemia . The hepatic expression of PPARα is nutritionally regulated: fasting activates PPARα, and fasted PPARα-null mice develop hypoglycaemia, hypoketonaemia, hyperlipidaemia and hepatic steatosis . As mentioned above, PPARα forms heterodimers with RXRα, which enhances its binding to peroxisome proliferator response elements in target genes . Thus, PPARα activation can suppress the LXRα-SREBP-1c pathway by interfering with the formation of SREBP-1c-activating LXR-RXR heterodimers  (Fig. 2).
Sterol regulatory element-binding protein 1c
SREBPs are membrane-bound transcription factors; they have been identified in three forms in humans and rodents. SREBP-1c and SREBP-2 are the predominant subtypes in the rodent and human liver . The main role of SREBP-2 is cholesterol synthesis, whereas SREBP-1c activates a complete programme of hepatic fatty acid synthesis  and reciprocally inhibits the expression of the gene for PEPCK when carbohydrates are abundant [69, 70]. Overexpression of the gene for SREBP-1c leads to fatty liver in mice .
SREBP-1c gene transcription is activated by insulin , probably mediated via IRS1, PI-3-K and protein kinase B (PKB/Akt) . The effect of insulin on expression of the SREBP-1c gene is opposed by glucagon . Changes in the expression of integral membrane proteins have been shown to inhibit the proteolytic activation of SREBPs. SREBP-1c is inhibited by activation of AMP-activated protein kinase (AMPK), a major cellular regulator of lipid and glucose metabolism (see below) . The promoter of the SREBP-1c gene contains a regulatory element for LXRα , which strongly induces its transcription . In turn, activated SREBP-1c stimulates the transcription of genes involved in de novo lipogenesis, such as ACAC and FASN, and interacts with regulatory elements in the promoters of various insulin-regulated genes. This involves competitive inhibition of PPARγ coactivator 1α (PGC-1α), a co-regulator that activates PEPCK promotor activity and gluconeogenesis . This effect of SREBP-1c seems to work in concert with insulin to suppress PGC-1α . However, elevated levels of SREBP-1c have also been shown to induce insulin resistance by inhibiting hepatic IRS2 signalling. A reduction in IRS2 expression restricts FOXO1 to the nucleus, leading to sustained gluconeogenesis . This, in turn, may activate SREBP-1c, ChREBP and lipogenic enzymes, leading to triglyceride accumulation in the liver.
Carbohydrate-response element-binding protein
The transcription factor ChREBP is translocated to the nucleus and activated in response to high glucose concentrations in the liver, independently of insulin. As the name suggests, it was first identified by its ability to bind the carbohydrate-response element of the gene encoding liver pyruvate kinase (L-PK). L-PK catalyses the conversion of phosphoenolpyruvate to pyruvate, which enters the Krebs cycle to generate citrate, the principal source of acetyl-CoA used for fatty acid synthesis . Insulin indirectly regulates ChREBP through activation of glucokinase, which allows phosphorylated glucose to enter the pentose phosphate cycle, generating xylulose 5-phosphate and activating ChREBP via protein phosphatase 2A . ChREBP has recently been shown to play a pivotal role in activating lipogenic genes . ChREBP binds to its functional heterodimeric partner, Max-like protein X, and induces the transcription of lipogenic and glycolytic genes containing a carbohydrate response element, such as those encoding ACAC, FASN and L-PK [3, 85].
11β-Hydroxysteroid dehydrogenase 1
11β-HSD1 is expressed in various—typically glucocorticoid-targeted—tissues. The highest levels of expression have been found in the liver, gonads, adipose tissue and the brain . In vivo, 11β-HSD1 converts inactive cortisone to active cortisol in humans (or inactive 11-dehydrocorticosterone to active corticosterone in rodents) and 11β-HSD2 catalyses the reverse reaction. Glucocorticoids, PPAR-γ agonists and proinflammatory cytokines increase 11β-HSD1 activity. Insulin has been shown to suppress expression of the gene for 11β-HSD1 (Hsd11b1) in rat hepatocytes and hepatoma cells, while oestrogens, growth hormone and insulin reduce Hsd11b1 expression in the rodent liver . Although subjects with obesity and the metabolic syndrome have normal circulating levels of cortisol, tissue-specific cortisol excess due to increased 11β-HSD1 activity has been suggested to explain the obvious phenotypic similarities with patients with glucocorticoid excess (Cushing’s syndrome) . In uncomplicated obesity, 11β-HSD1 activity has been proposed to be downregulated, probably as a compensatory mechanism to prevent insulin resistance. This downregulation may be disturbed in type 2 diabetic patients, leading to insulin resistance and increased fat deposition in various organs, including the liver .
Glucocorticoids are essential factors involved in energy homeostasis, with cortisol being the principal active glucocorticoid in humans. Glucocorticoids stimulate the transcription of glucogenic genes (including those for PEPCK and G-6-Pase [70, 93]), inhibit mitochondrial matrix acyl-CoA dehydrogenases and fatty acid β-oxidation, and may produce fatty liver in humans . In Cushing’s syndrome, increased glucocorticoid production and activation of the glucocorticoid receptor leads to obesity and insulin resistance. Antagonism of the receptor prevents obesity in rodents. Furthermore, a defect in 11β-HSD1 activity prevented a classical cushingoid phenotype in a patient with confirmed Cushing’s disease, despite the presence of systemic hypercortisolaemia .
AMP-activated protein kinase
AMP-activated protein kinase (AMPK) belongs to a family of highly conserved serine-threonine kinases and is present in various organs, including the liver . AMPK has a key role in the regulation of energy control as a metabolic sensor and regulator kinase. When activated, AMPK initiates a series of responses that are aimed at protecting the cell against ATP depletion, by stimulating fatty acid oxidation or glycolysis and inhibiting ATP-consuming anabolic pathways such as gluconeogenesis, protein and fatty acid synthesis . AMPK is phosphorylated and thereby activated by the protein–threonine kinase LKB1, which seems to be the major upstream AMPK-activating factor . Activation of AMPK results in inhibition of lipogenic factors such as SREBP-1c , FASN, ACAC  and ChREBP . Induction of AMPK in hepatoma cells also decreases PEPCK and G-6-Pase transcription, likely in an insulin-independent manner . AMPK is not known to be activated by insulin, raising the possibility that insulin and AMPK regulate PEPCK by different and, perhaps, converging pathways . AMPK may prevent insulin resistance in part by inhibiting factors that antagonise insulin signalling . Deletion of liver LKB1 in mice results in a near complete loss of AMPK activity, leading to lipogenic gene expression. Increased gluconeogenesis in these mice could be explained by the observed nuclear translocation of TORC2, which transcriptionally coactivates cAMP-response-element-binding protein (CREB), leading to increased expression of PGC-1α, thereby driving the expression of glucogenic genes .
A number of hormonal and nutritionally regulated factors have been proposed to be involved in the regulation of hepatic AMPK activity. The adipocyte-derived hormone adiponectin has been shown to activate AMPK (both in liver and skeletal muscle) and to reduce hepatic glucose production and the expression of hepatic gluconeogenic genes, while increasing β-oxidation of fatty acids in the liver [105, 106]. This may, at least in part, explain the positive associations between adiponectin and diabetes risk in epidemiological studies . Conversely, the orexigenic hormone ghrelin inhibits AMPK in the rat liver and in adipose tissue, while stimulating AMPK activity in the heart and hypothalamus . Ghrelin also decreases the effect of insulin on PEPCK in human hepatoma cells , and may therefore contribute to the development of hepatic insulin resistance and lipid accumulation. Other factors, such as adipocyte-secreted leptin or resistin (which is mainly expressed in monocytes and macrophages in humans) may be involved in the regulation of liver AMPK.
The studies discussed in this review indicate that hepatic fat accumulation, insulin resistance and disturbed glucose metabolism are inter-related at a molecular level. In insulin-resistant hyperglycaemic states the suppressive effects of insulin and glucose on hepatic glucose production is reduced, whereas undamped hepatic lipogenesis and non-insulin dependent glucose transport to the liver both contribute to hepatic lipid accumulation, which in turn may further deteriorate insulin signalling. Multiple organs, such as skeletal muscle, adipose tissue and the liver, are affected by insulin-resistant states and there has been considerable progress in identifying molecular pathways and potential factors involved. Skeletal muscle and fat tissue are relatively easily accessible for biopsy in humans. However, despite many similarities between molecular pathways in different tissues, there are also important differences. Thus, results obtained in other tissues cannot necessarily be transferred to the liver. Elucidating molecular pathways in human liver is more problematic due to the potential hazards involved in performing liver biopsies. It is therefore important to note that most studies that have investigated molecular pathways in the liver were performed in animal models or in vitro. Because molecular functions differ even between rodent species , it should be noted that, whilst results obtained in animal models provide valuable insights, they cannot necessarily be extrapolated to other species.
Due to limited space we only could discuss some of the key pathways. We apologise to all the researchers whose work was omitted because of constraints on the number of references. We would like to thank C. Loracher for intensive discussion of the subject.
Duality of interest statement
The authors are not aware of any duality of interest.
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