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

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an emerging epidemic in light of its two predisposing factors, a surge in both obesity and diabetes rates with reports of between 70-80% of obese individuals in Western countries. The disease progression of NAFLD remains elusive but is generally attributed to insulin resistance, lipid metabolism dysfunction, altered immune response to name a few. Potential therapeutic strategies should target one or some of these pathological events in the liver, however currently no specific therapies for NAFLD exist. Thus novel therapeutic approaches to manage the chronic liver disease epidemic are becoming essential. In this review we discuss the evidence supporting the role of bile acid activated Farnesoid X Receptor (FXR) in promoting lipid oxidation, reducing inflammation and fibrosis in the liver. We also examine the potential of FXR agonists, as an attractive class of drugs for the safe and effective treatment of NAFLD.

Gut Microbiota—A Future Therapeutic Target for People with Non-Alcoholic Fatty Liver Disease: A Systematic Review

“…In the liver, FXR activation results in the downregulation of free fatty acid (FFA) synthesis and de novo lipogenesis [ 45 ]. FXR is also involved in carbohydrate metabolism, as this regulates hepatic gluconeogenesis, and prevents hepatic inflammation [ 46 ].…”

The role of the gut microbiome and exercise in non-alcoholic fatty liver disease

“…Nowadays it is acknowledged that bile acids also have an important role in regulating lipid, carbohydrate, and cholesterol metabolism, and signaling pathways. 74 Bile acids can be categorized into primary and secondary bile acids. Primary bile acids are conjugated products from the liver bile acid pool, while secondary bile acids have been deconjugated by the gut microbiome.…”

“…A change in their metabolism and composition can lead to damaging effects on the liver. 27 , 74 It is also thought that farnesoid X receptor (FXR), a nuclear transcription factor of which bile acids are endogenous ligands, might play a role in NAFLD due to its impact on the oxidation of lipids and affect the metabolism of cholesterol and carbohydrates. 74 Furthermore, deletion of FXR leads to an increased inflammation in the liver in a WTD mice model 75 and development of HCC markers induced by a bile acid (cholic acid), 76 which indicates its pivotal role on the bile acid metabolism and the liver.…”

Fatty Liver Disease: A Crosstalk Between Lipid Species

“…45 Ceramide-1-P Cholesterol catabolism into bile acids begins with its conversion to 7-α-hydroxycholesterol by cholesterol 7-α-monooxygenase (CYP7A1), the rate-limiting step of the pathway. 46 Bile acids bind FXR, which represses CYP7A1, acting as a negative feedback loop. Besides its role in maintaining the balance between cholesterol and bile acids, FXR also induces lipolysis by activating PPAR-α and repressing SREBP-1c.…”