Dimethyl Sulfoxide Inhibits Bile Acid Synthesis in Healthy Mice but Does Not Protect Mice from Bile-Acid-Induced Liver Damage

SIMPLE SUMMARY: Bile acids are crucial in breaking down and absorbing fats. However, in excessive amounts, they can damage the liver. Our research investigated whether dimethyl sulfoxide (DMSO) could diminish bile acid production and subsequently protect the liver in mice. Our results showed that DMSO effectively reduced bile acid production in mouse primary hepatocytes and in vivo. Yet, DMSO failed to protect the liver when we evaluated its efficacy in two separate mouse models with liver damage induced or partially induced by excess bile acids. Notably, while DMSO decreases hepatic bile acid levels in healthy mice, the body appears to counterbalance this effect under disease conditions, resulting in persistent liver damage. These outcomes confirm that DMSO is not merely an inert solvent, but a biologically active agent. However, it falls short in treating liver diseases precipitated by elevated bile acid levels. ABSTRACT: Bile acids serve a vital function in lipid digestion and absorption; however, their accumulation can precipitate liver damage. In our study, we probed the effects of dimethyl sulfoxide (DMSO) on bile acid synthesis and the ensuing liver damage in mice induced by bile acids. Our findings indicate that DMSO efficaciously curbs bile acid synthesis by inhibiting key enzymes involved in the biosynthetic pathway, both in cultured primary hepatocytes and in vivo. Contrarily, we observed that DMSO treatment did not confer protection against bile-acid-induced liver damage in two distinct mouse models: one induced by a 0.1% DDC diet, leading to bile duct obstruction, and another induced by a CDA-HFD, resulting in non-alcoholic steatohepatitis (NASH). Histopathological and biochemical analyses unveiled a comparable extent of liver injury and fibrosis levels in DMSO-treated mice, characterized by similar levels of increase in Col1a1 and Acta2 expression and equivalent total liver collagen levels. These results suggest that, while DMSO can promptly inhibit bile acid synthesis in healthy mice, compensatory mechanisms might rapidly override this effect, negating any protective impact against bile-acid-induced liver damage in mice. Through these findings, our study underscores the need to reconsider treating DMSO as a mere inert solvent and prompts further exploration to identify more effective therapeutic strategies for the prevention and treatment of bile-acid-associated liver diseases.