PPARα activation partially drives NAFLD development in liver-specific Hnf4a-null mice. (23rd January 2023)

• Record Type: Journal Article
• Authors: Kasano-Camones, Carlos Ichiro; Takizawa, Masayuki; Ohshima, Noriyasu; Saito, Chinatsu; Iwasaki, Wakana; Nakagawa, Yuko; Fujitani, Yoshio; Yoshida, Ryo; Saito, Yoshifumi; Izumi, Takashi; Terawaki, Shin-Ichi; Sakaguchi, Masakiyo; Gonzalez, Frank J; Inoue, Yusuke
• Is Part Of: Journal of biochemistry. Volume 173:Number 5(2023)
• Page Start: 393
• Page End: 411
• Publication Date: 2023-01-23
• Subjects: Fatty acid -- Lipid -- Liver -- Nuclear receptor -- Steatohepatitis; Biochemistry -- Periodicals; Biochemistry -- Periodicals; Electronic journals; 572.05
• DOI: 10.1093/jb/mvad005
• Languages: English
• ISSNs: 0021-924X

Abstract

Abstract: HNF4α regulates various genes to maintain liver function. There have been reports linking HNF4α expression to the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis. In this study, liver-specific Hnf4a -deficient mice ( Hnf4a ΔHep mice) developed hepatosteatosis and liver fibrosis, and they were found to have difficulty utilizing glucose. In Hnf4a ΔHep mice, the expression of fatty acid oxidation-related genes, which are PPARα target genes, was increased in contrast to the decreased expression of PPARα, suggesting that Hnf4a ΔHep mice take up more lipids in the liver instead of glucose. Furthermore, Hnf4a ΔHep / Ppara −/− mice, which are simultaneously deficient in HNF4α and PPARα, showed improved hepatosteatosis and fibrosis. Increased C18:1 and C18:1/C18:0 ratio was observed in the livers of Hnf4a ΔHep mice, and the transactivation of PPARα target gene was induced by C18:1. When the C18:1/C18:0 ratio was close to that of Hnf4a ΔHep 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 PPARα activation in Hnf4a ΔHep mice. These insights may contribute to the development of new diagnostic and therapeutic approaches for NAFLD by focusing on the HNF4α and PPARα signaling cascade. Graphical Abstract: