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New insights into the bile acid-based regulatory mechanisms and therapeutic perspectives in alcohol-related liver disease

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Abstract

Cholestasis is a key causative factor in alcohol-related liver disease (ALD) and variable degrees of cholestasis occur in all stages of ALD. However, the pathogenetic mechanisms and biomarkers associated with cholestasis are not well characterized. Cholestatic disease is marked by the disruption of bile acids (BA) transport and homeostasis. Consequently, in both human and experimental ALD, the disease shows a direct correlation with an imbalance in BA equilibrium, which in turn may also affect the severity of the disease. Modulation of BA metabolism or signaling pathways is increasingly considered as a potential therapeutic strategy for ALD in humans. In this paper, we highlight the key advances made in the past two decades in characterizing the molecular regulatory mechanisms of BA synthesis, enterohepatic circulation, and BA homeostasis. We summarize recent insights into the nature of the linkage between BA dysregulation and ALD, including the abnormal expression of genes involved in BA metabolism, abnormal changes in receptors that regulate BA metabolism, and disturbance in the gut flora engaged in BA metabolism caused by alcohol consumption. Additionally, we provide novel perspectives on the changes in BAs in various stages of ALD. Finally, we propose potential pharmacological therapies for ALD targeting BA metabolism and signaling.

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Abbreviations

ABCB4:

ATP-binding cassette subfamily B member 4

ACLF:

Acute-on-chronic liver failure

ACLI:

Acute-on-chronic liver injury

AD:

Acute decompensation

ADH:

Alcohol dehydrogenase

AFLD:

Alcoholic fatty liver disease

AH:

Alcoholic hepatitis

ALD:

Alcohol-related liver disease

ALDH:

Acetaldehyde dehydrogenase

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

ASBT:

Apical sodium-dependent BA transporter

ASCA:

Anti-Saccharomyces cerevisiae antibodies

ASH:

Alcoholic steatohepatitis

AST:

Aspartate aminotransferase

AUDs:

Alcohol use disorders

BA:

Bile acids

BAAT:

Bile acid-CoA: amino acid N-acyltransferase

BACS:

Bile acid-CoA synthetase

BSEP:

Bile salt export pump

BSH:

Bile salt hydrolase

CA:

Cholic acid

CB1R:

Cannabinoid receptor type 1

CDCA:

Chenodeoxycholic acid

COX-2:

Cyclooxygenase-2

CREBH:

CAMP response element-binding protein hepatocyte-specific

CYP2E1:

Cytochrome P450 2E1 enzyme

CYP7A1:

Cholesterol 7α-hydroxylase

CYP8B1:

Sterol 12α-hydroxylase

DAMPs:

Damage-associated molecular patterns

DCA:

Deoxycholic acid

ERK1/2:

Extracellular regulated protein kinases 1/2

FGF15/19:

Fibroblast growth factor 15/19

FGF21:

Fibroblast growth factor 21

FGR4:

Fibroblast growth factor receptor 4

FIB-4:

Fibrosis4Score

FOXP3:

Forkhead box protein 3

FXR:

Farnesoid X receptor

GCA:

Glycocholic acid

GCDCA:

Glycochenodeoxycholic acid

GDCA:

Glycodeoxycholic acid

GGT:

Gamma-glutamyl-transferase

GLCA:

Glycolithocholic acid

GLP1:

Glucagon-like peptide-1

HCA:

Hyocholic acid

HCC:

Hepatocellular carcinoma

HSC:

Hepatic stellate cells

IM:

Intestinal microbiota

LCA:

Lithocholic acid

LRH-1:

Liver receptor homolog-1

LTA:

Lipoteichoic acid

MAFLD:

Metabolic-associated fatty liver disease

MCD:

Methionine-choline-deficient diet

MCRS1:

Microspherule protein 1

MELD:

Model for end-stage liver disease

MEOS:

Microsomal ethanol oxidation system

MRP3/4:

Multidrug resistance-associated protein 3/4

NAFL:

Non-alcoholic fatty liver

NASH:

Non-alcoholic steatohepatitis

NF-κB:

Nuclear transcription factor-κB

NLRs:

Nod-like receptors

NTCP:

Sodium/taurocholate cotransporting polypeptide

OSTα/β:

Organic solute transporter α/β

PAMPs:

Pathogen-associated molecular patterns

PBC:

Primary biliary cirrhosis

PDC:

Pyruvate dehydrogenase complex

PDK4:

Pyruvate dehydrogenase kinase 4

PGE2:

Prostaglandin E2

PPAR:

Peroxisome proliferator-activated receptor

PSC:

Primary sclerosing cholangitis

PTGER4:

Prostaglandin E receptor 4

ROC:

Receiver operating characteristic

RORγt:

Retinoic acid receptor-related orphan receptor- γ t

ROS:

Reactive oxygen species

RXRα:

Retinoid X receptor-α

SASP:

Senescence-associated secretory phenotype

SHP:

Small heterodimer partner

SIRT1:

Sirtuins 1

SIRT5:

Sirtuins 5

TBA:

Total BA

TCA:

Taurocholic acid

TCDCA:

Taurochenodeoxycholic acid

TDCA:

Taurodeoxycholic acid

TGR5:

Takeda G protein-coupled receptor 5

TLCA:

Taurolithocholic acid

TLR4:

Toll-like receptor 4

TLRs:

Toll-like receptors

Treg:

Regulatory T cell

UDCA:

Ursodeoxycholic acid

β-MCA:

β-Muricholic acid

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This work was sponsored by the National Natural Science Foundation of China (Grants nos. 81972265, 82170602), the National Natural Science Foundation of Jilin Province (20200201324JC), and the Project for Health Talents of Jilin Province (JLSWSRCZX 2021-079).

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  1. Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, 130021, Jilin, China

    Yali Liu, Tao Liu, Xu Zhao & Yanhang Gao

  2. Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China

    Yanhang Gao

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All authors contributed to the study conception and design. YG designed the review outline; YG and YL drafted the manuscript; YG, YL, TL, and XZ revised and edited the paper. All the authors read and approved the final manuscript.

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Liu, Y., Liu, T., Zhao, X. et al. New insights into the bile acid-based regulatory mechanisms and therapeutic perspectives in alcohol-related liver disease. Cell. Mol. Life Sci. 79, 486 (2022). https://doi.org/10.1007/s00018-022-04509-6

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