HIF-1-dependent lipin1 induction prevents excessive lipid accumulation in choline-deficient diet-induced fatty liver

• Published in: Scientific reports Vol. 8; no. 1; pp. 14230 - 9
• Main Authors: Arai, Takatomo, Tanaka, Masako, Goda, Nobuhito
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 21.09.2018; Nature Publishing Group UK
• Subjects: Adaptation; Choline; Clonal deletion; Diet; Fatty liver; Hypoxia; Hypoxia-inducible factor 1; Lipid metabolism; Lipids; Liver; Liver diseases; Metabolism; Nutrient deficiency; Oxidation; Rodents; Steatosis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-32586-w

Adaptive responses to hypoxia regulate hepatic lipid metabolism, but their consequences in nonalcoholic fatty liver disease (NAFLD) are largely unknown. Here, we show that hypoxia inducible factor-1 (HIF-1), a key determinant of hypoxic adaptations, prevents excessive hepatic lipid accumulation in the progression of NAFLD. When exposed to a choline-deficient diet (CDD) for 4 weeks, the loss of hepatic Hif-1α gene accelerated liver steatosis with enhanced triglyceride accumulation in the liver compared to wild-type (WT) livers. Expression of genes involved in peroxisomal fatty acid oxidation was suppressed significantly in CDD-treated WT livers, whereas this reduction was further enhanced in Hif-1α-deficient livers. A lack of induction and nuclear accumulation of lipin1, a key regulator of the PPARα/PGC-1α pathway, could be attributed to impaired peroxisomal β-oxidation in Hif-1α-deficient livers. The lipin1-mediated binding of PPARα to the acyl CoA oxidase promoter was markedly reduced in Hif-1α-deficient mice exposed to a CDD. Moreover, forced Lipin1 expression restored the aberrant lipid accumulation caused by Hif-1α deletion in cells incubated in a choline-deficient medium. These results strongly suggest that HIF-1 plays a crucial role in the regulation of peroxisomal lipid metabolism by activating the expression and nuclear accumulation of lipin1 in NAFLD.