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

Abstract

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.

SIRT3 deficiency exacerbates fatty liver by attenuating the HIF1α-LIPIN 1 pathway and increasing CD36 through Nrf2

“…In this study we report that feeding Sirt3-deficient mice the HFD also results in enhanced levels of the mature SREBP1 form, although the increase did not reach significance. This finding was consistent with the increase in phospho-mTOR levels in these animals, since mTORC1 regulates nuclear LIPIN 1 localization to control nuclear SREBP1c abundance [26] and also regulates the processing of SREBP1c to its mature form [27]. The slight increase in SREBP1c abundance did not significantly affect the expression of genes involved in lipogenesis.…”

“…By contrast, LIPIN 1 in the nucleus acts as a transcriptional co-activator linked to fatty acid oxidation by upregulating PPARα activity, thereby ultimately increasing the expression of its target genes, including Mcad and Cpt-1α [25]. Previous studies have reported that hypoxia-inducible factor (HIF)-1α regulates LIPIN 1 levels and localization [26,27]. Moreover, SIRT3 loss represses prolyl hydroxylase domain enzymes, thus leading to increased levels of HIF-1α [28,29].…”

“…The lack of induction in PPARα in the liver of Sirt3- deficient mice fed the HFD might involve a decrease in the nuclear levels of LIPIN 1, a PPARα transcriptional co-activator [ 25 ]. LIPIN 1 levels and localization are regulated by HIF-1α [ 26 , 27 ], a transcription factor, which in turn is upregulated by the loss of Sirt3 [ 28 , 29 ]. The lack of increase in nuclear LIPIN 1 in the liver of Sirt3- deficient mice fed the HFD was accompanied by a decrease in HIF-1α compared to Sirt3- deficient mice fed a standard diet.…”

Smurf1 aggravates non‐alcoholic fatty liver disease by stabilizing SREBP‐1c in an E3 activity‐independent manner

“…Non‐alcoholic fatty liver disease (NAFLD) is currently one of the most common chronic liver diseases with a global incidence of approximately 25% 1 . The hallmark of NAFLD is excessive lipid accumulation due to an imbalance between lipogenesis and lipolysis in hepatocytes 2 . Lipogenesis is controlled primarily at the transcriptional level 3 .…”

Hypoxia and Non-alcoholic Fatty Liver Disease

“…Regarding HIF1α, a number of experimental studies in distinct murine models have shown that either systemic or hepatic Hifa genetic deletion or HIF1α antisense oligonucleotide treatment decreased hepatosteatosis, suggesting the potential of HIF1α inhibition for the treatment of NAFLD (24,25). Conversely, other studies have revealed that HIF1α protected against alcohol or choline deprivation-induced fatty liver (26,27), so further investigations are needed to clarify the impact of HIF1α in hepatosteatosis setup.…”