PPARα activation partially drives NAFLD development in liver-specific Hnf4a-null mice

HNF4 alpha regulates various genes to maintain liver function. There have been reports linking HNF4 alpha expression to the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis. In this study, liver-specific Hnf4a-deficient mice (Hnf4a(Delta Hep) mice) developed hepatosteatosis and liver fibrosis, and they were found to have difficulty utilizing glucose. In Hnf4a(Delta Hep) mice, the expression of fatty acid oxidation-related genes, which are PPAR alpha target genes, was increased in contrast to the decreased expression of PPAR alpha, suggesting that Hnf4a(Delta Hep) mice take up more lipids in the liver instead of glucose. Furthermore, Hnf4a(Delta Hep)/Ppara(-/-) mice, which are simultaneously deficient in HNF4 alpha and PPAR alpha, showed improved hepatosteatosis and fibrosis. Increased C18:1 and C18:1/C18:0 ratio was observed in the livers of Hnf4a(Delta Hep) mice, and the transactivation of PPAR alpha target gene was induced by C18:1. When the C18:1/C18:0 ratio was close to that of Hnf4a(Delta Hep) mouse liver, a significant increase in transactivation was observed. In addition, the expression of Pgc1a, a coactivator of PPARs, was increased, suggesting that elevated C18:1 and Pgc1a expression could contribute to PPAR alpha activation in Hnf4a(Delta Hep) mice. These insights may contribute to the development of new diagnostic and therapeutic approaches for NAFLD by focusing on the HNF4 alpha and PPAR alpha signaling cascade.

Automated summary

HNF4 alpha plays a crucial role in regulating liver function and has been linked to the development of NAFLD and NASH. Liver-specific Hnf4a-deficient mice showed hepatosteatosis, liver fibrosis, and impaired glucose utilization. Additionally, the study found that simultaneous deficiency of HNF4 alpha and PPAR alpha improved hepatosteatosis and fibrosis.