Therapeutic modulation of the bile acid pool byCyp8b1knockdown protects against nonalcoholic fatty liver disease in mice

What is it about?

During the ingestion of food, a mixture of bile acids (BA) is released by the gallbladder to facilitate the intestinal absorption of hydrophobic nutrients such as lipids. The BA pool is derived from two primary bile acids, cholic acid (CA) and chenodeoxycholic acid. The balance between these two BAs is tightly controlled by the hepatic protein CYP8B1, allowing for the adaptation of the BA pool to bodily needs. CYP8B1 is critical to the regulation of lipid metabolism and increased plasma levels of CA-derived BAs have been observed in patients with non-alcoholic fatty liver disease (NAFLD). NAFLD is characterized by the accumulation of hepatic lipids, and NAFLD-derived cirrhosis is expected to become the leading cause of liver transplantation in developed countries. In this study, we developed and used small interfering RNA (siRNA) to inhibit the expression of the Cyp8b1 gene in mice. By inhibiting Cyp8b1, we aimed at modifying the BA pool composition to reduce fat absorption, and we evaluated our treatment in a mouse model of cholesterol-induced NAFLD. Intravenous injections of Cyp8b1 siRNA led to a profound remodeling of the BA pool, and decreased dietary fat absorption. In mice fed a high cholesterol diet, Cyp8b1 siRNA treatment led to the inhibition, and even to the regression of NAFLD. Our study demonstrates that CYP8B1 may be a valuable therapeutic target for the treatment of NAFLD. As bile acid metabolism differs between mice and humans, further studies are required to validate our findings before translating them to the clinic.

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