Therapeutic potential of tetrahydroxylated bile acids in reducing liver injury: Insights from the Zfyve19 −/− mouse model

ABSTRACT Importance The production of tetrahydroxylated bile acids (THBAs) is associated with better prognosis in some cholestatic patients as well as in multidrug resistance protein 2 knockout ( Mdr2 −/− ) mice. However, it remains unclear whether this protective effect is specific to Mdr2 −/− mice. Objective To evaluate the effects of THBA (3α,6α,7α,12α‐Tetrahydroxy‐10β,13β‐pentanoic acid) in Zfyve19 −/− mice, a newly developed mouse model characterized by cholestatic liver injury. Methods THBA was administered to Zfyve19 −/− mice challenged with alpha‐naphthyl isothiocyanate (ANIT). Serum biochemistry, liver histology and immunostaining, and quantitative PCR for hepatic expression of pro‐fibrotic, pro‐inflammatory, and bile acid metabolism‐related genes were performed and compared against ANIT‐treated wild‐type and Zfyve19 −/− mice fed normal chow. Results THBA administration reduced serum alanine aminotransferase ( P < 0.001) and total bile acid levels ( P < 0.001), decreased necrosis ( P = 0.046), portal inflammation ( P < 0.001), bile duct hyperplasia ( P = 0.007), and portal fibrosis ( P = 0.002) in liver histology, along with a significant reduction in hepatic expression of pro‐fibrotic genes ( Acta2 , Col1a1 , Tgfb1 , Tgfb2 , and Timp1 ), as well as the pro‐inflammatory cytokines Tnf and macrophage chemokines ( Ccl2 , Cxcl1 , Cxcl9 , Cxcl10 , and Nos2 ). Additionally, the mRNA expression of Nr1h4 was profoundly upregulated, while key enzymes involved in bile acid synthesis were downregulated. Interpretation THBA effectively alleviated cholestatic liver injury and fibrosis, and may represent a potential agent for the medical management of such diseases.