Non-Alcoholic Fatty Liver Disease: The Effect of Bile Acids and Farnesoid X Receptor Agonists on Pathophysiology and Treatment

Non-alcoholic fatty liver disease (NAFLD) is a complex disease, affecting not just the liver, but also all other organs in the body. Despite an increasing amount of people worldwide developing NAFLD and having it progress to non-alcoholic steatohepatitis (NASH) and potentially cirrhosis, there is still no approved therapy. Therefore, huge efforts are being made to find and develop a successful treatment. One of the special interests is understanding the liver–gut axis and especially the role of bile acids in the progression of NAFLD. Farnesoid X receptor (FXR)-agonists have been approved und used in other liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), and have shown signs of being able to decrease inflammation and potentially steatosis. This review will mainly focus on targets/ligands that play an important role in bile acid metabolism and give an overview of ongoing clinical as well as pre-clinical trials. With the complexity of the issue, we did not aim at giving a complete review, rather highlighting important targets and potential treatments that could be approved for NAFLD/NASH treatment within the next few years.

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A look at new therapeutic opportunities in patients with non-alcoholic fatty liver disease

Obesity and metabolism ◽

10.14341/omet9986 ◽

2019 ◽

Vol 16 (3) ◽

pp. 37-45

Author(s):

Ekaterina E. Mishina ◽

Alexander Y. Mayorov ◽

Apollinariya V. Bogolyubova ◽

Pavel O. Bogomolov ◽

Maria V. Matsievich ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Alcoholic Fatty Liver ◽

Inflammatory Processes ◽

Active Research ◽

Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and is considered to be the liver manifestation of metabolic syndrome. Currently, there is no etiotropic treatment of NAFLD, so an active research for new methods of treatment is underway. In the meantime, drugs are used to treat comorbid conditions, such as dyslipidemia, arterial hypertension, obesity, type 2 diabetes, which are present in varying degrees in patients. This review considers medications that are used in patients with NAFLD and related concomitant features, and also describes new strategies for regressing changes in liver tissue in NAFLD. In our opinion, one of the promising groups of drugs are agonists of the farnesoid X receptor (FXR). FXR belongs to the group of nuclear receptors, which are ligand-activated transcription factors that regulate the genes involved in metabolism. FXR agonists can claim to be a new promising drug for the treatment of NAFLD and related diseases influencing carbohydrate metabolism, fat metabolism, bile acid metabolism, as well as inflammatory processes in the liver to ensure metabolic homeostasis.

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Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression

Metabolism ◽

10.1016/j.metabol.2020.154457 ◽

2021 ◽

Vol 116 ◽

pp. 154457

Author(s):

Nisreen Nimer ◽

Ibrahim Choucair ◽

Zeneng Wang ◽

Ina Nemet ◽

Lin Li ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Disease Progression ◽

Bile Acids ◽

Genetic Variants ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Liver Disease Progression ◽

Alcoholic Fatty Liver Disease

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EDP-305, a novel and highly potent farnesoid X receptor agonist, improves liver steatosis, ballooning and non-alcoholic fatty liver disease (NAFLD) activity score (NAS) in a diet-induced murine model of non-alcoholic steatohepatitis

Journal of Hepatology ◽

10.1016/s0168-8278(17)31237-0 ◽

2017 ◽

Vol 66 (1) ◽

pp. S434

Author(s):

L.-J. Jiang ◽

M. Chau ◽

Y. Li ◽

F. Briand ◽

T. Sulpice ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Murine Model ◽

Fatty Liver Disease ◽

Receptor Agonist ◽

Liver Steatosis ◽

Farnesoid X Receptor ◽

Alcoholic Fatty Liver ◽

Nafld Activity Score ◽

Alcoholic Fatty Liver Disease

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Bile Acids and Dysbiosis in Non-Alcoholic Fatty Liver Disease

PLoS ONE ◽

10.1371/journal.pone.0151829 ◽

2016 ◽

Vol 11 (5) ◽

pp. e0151829 ◽

Cited By ~ 132

Author(s):

Marialena Mouzaki ◽

Alice Y. Wang ◽

Robert Bandsma ◽

Elena M. Comelli ◽

Bianca M. Arendt ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Bile Acids ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

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New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease

Expert Opinion on Pharmacotherapy ◽

10.1517/14656566.2014.876992 ◽

2014 ◽

Vol 15 (4) ◽

pp. 493-503 ◽

Cited By ~ 114

Author(s):

Amirhossein Sahebkar ◽

Gerard T Chew ◽

Gerald F Watts

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Atherogenic Dyslipidemia ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Alcoholic Fatty Liver ◽

Receptor Agonists ◽

Alcoholic Fatty Liver Disease

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Bile acids serum levels in patients with nonalcoholic fatty liver disease

Kazan medical journal ◽

10.17750/kmj2015-354 ◽

2015 ◽

Vol 96 (3) ◽

pp. 354-358 ◽

Cited By ~ 1

Author(s):

Z Sh Minnullina ◽

S V Kiyashko ◽

O V Ryzhkova ◽

R G Sayfutdinov

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Bile Acids ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Serum Levels ◽

Healthy Individuals ◽

Alcoholic Fatty Liver ◽

Significant Difference ◽

Alcoholic Fatty Liver Disease

Aim. To estimate the blood levels of primary, secondary, tertiary and unconjugated bile acids in patients with non-alcoholic fatty liver disease.Methods. The study included 74 patients with non-alcoholic fatty liver disease (males - 30, females - 44) and 51 healthy individuals (males - 14, females - 37). All patients underwent anthropometry and complete clinical, biochemical and instrumental examination (measuring the subcutaneous fat layer). 64 patients had hepatic steatosis, 10 - steatohepatitis. Serum levels of bile acids (primary: cholic, chenodeoxycholic; secondary: lithocholic, deoxycholic and tertiary: ursodeoxycholic) were measured by gas-liquid chromatography on «Chromos GC-1000» (Russia) scanner.Results. Unconjugated primary, secondary and tertiary bile acids were detected in the blood of healthy individuals and patients with non-alcoholic fatty liver disease. In healthy individuals, there were no gender differences found in the bile acids levels. Patients with non-alcoholic fatty liver disease had higher level of bile acids compared to healthy controls. There was a significant difference in the concentrations of secondary and tertiary bile acids in patients with hepatic steatosis and steatohepatitis.Conclusion. Blood bile acids levels were significantly higher in patients with non-alcoholic fatty liver disease than in healthy individuals. At steatohepatitis, females had higher levels of cholic, chenodeoxycholic and deoxycholic acids and lower levels of lithocholic and ursodeoxycholic acids compared to males. Significant difference in patients with hepatic steatosis and steatohepatitis was revealed only in levels of secondary and tertiary bile acids.

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Aryl Hydrocarbon Receptor (AhR) Activation by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Dose-Dependently Shifts the Gut Microbiome Consistent with the Progression of Non-Alcoholic Fatty Liver Disease

International Journal of Molecular Sciences ◽

10.3390/ijms222212431 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12431

Author(s):

Russell R. Fling ◽

Timothy R. Zacharewski

Keyword(s):

Liver Disease ◽

Bile Acid ◽

Fatty Liver ◽

Bile Acids ◽

Fatty Liver Disease ◽

Acid Metabolism ◽

Bile Acid Metabolism ◽

Alcoholic Fatty Liver ◽

Dose Dependent ◽

Alcoholic Fatty Liver Disease

Gut dysbiosis with disrupted enterohepatic bile acid metabolism is commonly associated with non-alcoholic fatty liver disease (NAFLD) and recapitulated in a NAFLD-phenotype elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. TCDD induces hepatic fat accumulation and increases levels of secondary bile acids, including taurolithocholic acid and deoxycholic acid (microbial modified bile acids involved in host bile acid regulation signaling pathways). To investigate the effects of TCDD on the gut microbiota, the cecum contents of male C57BL/6 mice orally gavaged with sesame oil vehicle or 0.3, 3, or 30 µg/kg TCDD were examined using shotgun metagenomic sequencing. Taxonomic analysis identified dose-dependent increases in Lactobacillus species (i.e., Lactobacillus reuteri). Increased species were also associated with dose-dependent increases in bile salt hydrolase sequences, responsible for deconjugation reactions in secondary bile acid metabolism. Increased L. reuteri levels were further associated with mevalonate-dependent isopentenyl diphosphate (IPP) biosynthesis and o-succinylbenzoate synthase, a menaquinone biosynthesis associated gene. Analysis of the gut microbiomes from cirrhosis patients identified an increased abundance of genes from the mevalonate-dependent IPP biosynthesis as well as several other menaquinone biosynthesis genes, including o-succinylbenzoate synthase. These results extend the association of lactobacilli with the AhR/intestinal axis in NAFLD progression and highlight the similarities between TCDD-elicited phenotypes in mice to human NAFLD.

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