A study published in the journal Cell Metabolism finds that hyodeoxycholic acid alleviates non-alcoholic fatty liver disease by modulating the gut-liver axis.
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent disease that can progress to severe liver adversities, including hepatic steatohepatitis, cirrhosis, and hepatic cancer. The development and progression of this disease are associated with a set of complex and heterogeneous processes. To date, clinically approved anti-NAFLD medicines are not available worldwide.
Bile acids are synthesized from cholesterol in the liver, released in the intestine, and further metabolized by the gut microbiota. The bile acid-gut microbiota interaction plays a vital role in regulating glucose and lipid metabolism.
A semi-synthetic bile acid analog namely obeticholic acid has shown promising outcomes in treating NAFLD in clinical trials. However, adverse side effects associated with long-term obeticholic acid treatment restrict its widespread usage as an anti-NAFLD medicine.
Previously, a special cluster of non-12α-hydroxylated bile acids, including hyocholic acid (HCA), and hyodeoxycholic acid (HDCA) species, has been identified. These bile acids, which are derived from the CYP7B1-centered alternative bile acid synthesis pathway, exhibit high efficacy in regulating glucose metabolism and predicting type 2 diabetes.
In this study, scientists have investigated the therapeutic efficacy and mode of action of HDCA in mouse models of NAFLD.
The association between serum levels of bile acids and the presence of NAFLD was assessed in a group of participants, including 178 NAFLD patients and 73 healthy individuals. The findings revealed that patients with NAFLD have significantly lower serum levels of HCA species, especially HDCA and glycohyodeoxycholic acid (GHDCA).
The serum levels of HCA species were further measured in two mouse models of hepatic steatosis. In the long-term high-fat diet model, a gradual deterioration in liver condition and reduction in HDCA levels were observed over time. Similar findings were obtained from the other model (STAM model) that mimics NAFLD progression in humans.
Overall, the clinical and animal data revealed an association between NAFLD and lower serum and hepatic levels of HDCA. Given these observations, scientists further investigated the therapeutic potential of HDCA against NAFLD.
Therapeutic efficacy of HDCA
The treatment of high-fat diet-fed hepatic steatosis mice with HDCA or HDCA-enriched pig bile powder led to a significantly reduced accumulation of excess lipid droplets in hepatocytes and liver weight.
Moreover, both treatments caused a reduction in serum biomarkers of liver damage, including aspartate transaminase (AST) and alanine transaminase (ALT). An improvement in glucose tolerance and insulin sensitivity was also observed in HDCA- and bile powder-treated mice.
Alternative bile acid synthetic pathway
RNA sequencing and functional pathway analysis of liver tissues obtained from HDCA- and bile powder-treated high-fat diet-fed mice revealed that both HDCA and bile powder had a significant impact on the primary bile acid biosynthesis pathway.
Specifically, significant upregulation of Cyp7b1 and downregulation of Cyp7a1 were observed, indicating an HDCA-mediated shift from the classic bile acid synthesis pathway to an alternative pathway.
Further experiments in Cyp7b1-overexpressing and Cyp7b1-knockout mice revealed that HDCA-mediated improvement in hepatic steatosis is associated with Cyp7b1-induced activation of the alternative bile acid synthesis pathway.
Available evidence indicates that the intestinal farnesoid X receptor (FXR) pathway regulates bile acid synthesis and that HCA species can inhibit FXR-fibroblast growth factor 15 (FGF15) signaling.
Consistent with these observations, this study also found that both HDCA and bile powder inhibited intestinal FXR signaling in different mouse models. Moreover, HDCA was found to impact gut microbiota composition, as evidenced by an increased abundance of gut microbe Parabacteroides distasonis in HDCA-treated mice.
Further experiments indicated that Parabacteroides distasonis abundance is positively associated with unsaturated fatty acid synthesis. The analysis of liver transcription factors in HDCA-treated mice showed a significant upregulation in hepatic transcription factor peroxisome proliferator-activated receptor alpha (PPARα) and its target genes.
Further experiments indicated that Parabacteroides distasonis-derived fatty acids, such as γ-linolenic acid, activated hepatic PPARα, which subsequently activated the hepatic FXR signaling in response to HDCA.
The study finds the pharmacological efficacy of an endogenous bile acid species, HDCA, in managing NAFLD. HDCA-mediated inhibition of intestinal FXR signaling is associated with the activation of hepatic classic and alternative bile acid synthesis pathways.
Moreover, HDCA increases the abundance of probiotic species Parabacteroides distasonis in the gut microbiota, which produces fatty acids that inhibit the hepatic Cyp7a1-mediated classic bile acid synthesis pathway through PPARα signaling.