| First Author | Arai T | Year | 2018 |
| Journal | Sci Rep | Volume | 8 |
| Issue | 1 | Pages | 14230 |
| PubMed ID | 30242180 | Mgi Jnum | J:295654 |
| Mgi Id | MGI:6454178 | Doi | 10.1038/s41598-018-32586-w |
| Citation | Arai T, et al. (2018) HIF-1-dependent lipin1 induction prevents excessive lipid accumulation in choline-deficient diet-induced fatty liver. Sci Rep 8(1):14230 |
| abstractText | 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-1alpha 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-1alpha-deficient livers. A lack of induction and nuclear accumulation of lipin1, a key regulator of the PPARalpha/PGC-1alpha pathway, could be attributed to impaired peroxisomal beta-oxidation in Hif-1alpha-deficient livers. The lipin1-mediated binding of PPARalpha to the acyl CoA oxidase promoter was markedly reduced in Hif-1alpha-deficient mice exposed to a CDD. Moreover, forced Lipin1 expression restored the aberrant lipid accumulation caused by Hif-1alpha 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. |
