Bile Acid Receptors and the Gut–Liver Axis in Nonalcoholic Fatty Liver Disease

Abstract

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been significantly increased due to the global epidemic of obesity. The disease progression from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is closely linked to inflammation, insulin resistance, and dysbiosis. Although extensive efforts have been aimed at elucidating the pathological mechanisms of NAFLD disease progression, current understanding remains incomplete, and no effective therapy is available. Bile acids (BAs) are not only important physiological detergents for the absorption of lipid-soluble nutrients in the intestine but also metabolic regulators. During the last two decades, BAs have been identified as important signaling molecules involved in lipid, glucose, and energy metabolism. Dysregulation of BA homeostasis has been associated with NAFLD disease severity. Identification of nuclear receptors and G-protein-coupled receptors activated by different BAs not only significantly expanded the current understanding of NAFLD/NASH disease progression but also provided the opportunity to develop potential therapeutics for NAFLD/NASH. In this review, we will summarize the recent studies with a focus on BA-mediated signaling pathways in NAFLD/NASH. Furthermore, the therapeutic implications of targeting BA-mediated signaling pathways for NAFLD will also be discussed.

Bile acids and sphingolipids in non-alcoholic fatty liver disease

“…Enterohepatic circulation involves the secretion of bile acids from the gallbladder to the intestinal lumen, where bile acids facilitate lipid-soluble nutrient absorption. More than 95% of bile acids are reabsorbed by enterocytes in the terminal ileum and transported to the liver via the portal vein [23,32] . About 5% of bile acids escape reabsorption and will be transformed into a variety of secondary bile acids by gut bacteria via deconjugation, oxidation, esterification, epimerization, and desulfation.…”

“…In addition, b-MCA also can be transformed into v-MCA, hyocholic acid, and hyodeoxycholic acid. The 5% of bile acids excreted in feces are replaced through de-novo synthesis in the liver [23] [Figure 2]. Bile acids are not only detergents but are also important signaling molecules.…”

“…In the past 2 decades, numerous studies have shown that bile acid-mediated activation of the nuclear receptor, farnesoid X receptor (FXR), and G protein-coupled receptors (GPCRs), Takeda G-protein- coupled receptor 5 (TGR5) and sphingosine-1 phosphate receptor 2 (S1PR2), play important roles in the progression of NAFLD and other metabolic diseases via modulating hepatic lipid metabolism, immune responses, and the gut microbiome. [22,23,33] Sphingolipid metabolism and signaling pathways Sphingolipids are essential structural components of all eukaryotic membranes. The synthetic pathways of sphingolipids have been well characterized.…”

“…[17][18][19][20] Furthermore, the role of bile acid-mediated signaling pathways in NAFLD has recently been extensively discussed. [22,23] In this review, we will highlight the recent advances in the sphingolipid field and discuss connections between bile acids and sphingolipid signaling with a focus on NAFLD.…”

Transcriptional Regulation of Hepatic Autophagy by Nuclear Receptors

“…They are either ligand-dependent or -independent transcription factors that play key roles in almost every mammalian physiology. Dysfunctions of nuclear receptor (NR) signaling pathways often become culprits that lead to many human diseases including liver diseases [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. For a long time, autophagy regulation has been considered to exclusively occur in cytoplasm.…”