Butyrate Attenuates Hepatic Steatosis Induced by a High‐Fat and Fiber‐Deficient Diet via the Hepatic GPR41/43‐CaMKII/HDAC1‐CREB Pathway

SCOPE: Hepatic steatosis is a major health issue that can be attenuated by a healthy diet. This study investigates the effects and molecular mechanisms of butyrate, a dietary fiber metabolite of gut microbiota, on lipid metabolism in hepatocytes. METHODS AND RESULTS: This study examines the effects of butyrate (0–8 mM) on lipid metabolism in primary hepatocytes. The results show that butyrate (2 mM) consistently inhibits lipogenic genes and activates lipid oxidation‐related gene expression in hepatocytes. Furthermore, butyrate modulates lipid metabolism genes, reduces fat droplet accumulation, and activates the calcium/calmodulin‐dependent protein kinase II (CaMKII)/histone deacetylase 1 (HDAC1)‐cyclic adenosine monophosphate response element binding protein (CREB) signaling pathway in the primary hepatocytes and liver of wild‐type (WT) mice, but not in G‐protein‐coupled receptor 41 (GPR41) knockout and 43 (GPR43) knockout mice. This suggests that butyrate regulated hepatic lipid metabolism requires GPR41 and GPR43. Finally, the study finds that dietary butyrate supplementation (5%) ameliorates hepatic steatosis and abnormal lipid metabolism in the liver of mice fed a high‐fat and fiber‐deficient diet for 15 weeks. CONCLUSION: This work reveals that butyrate improves hepatic lipid metabolism through the GPR41/43‐CaMKII/HDAC1‐CREB pathway, providing support for consideration of butyrate as a dietary supplement to prevent the progression of NAFLD induced by the Western‐style diet.