Gut inflammation exacerbates high-fat diet induced steatosis by suppressing VLDL-TG secretion through HNF4α pathway.

Nonalcoholic fatty liver disease (NAFLD) is increasingly identified in inflammatory bowel disease (IBD) patients with unclear etiology. In the current study we assessed the contribution of colonic inflammation to NAFLD development and the underlying mechanism in a mouse model for IBD. Our results showed that dextran sulfate sodium (DSS)-induced gut colitis directly led to hepatic inflammation, injury and further exacerbated hepatic steatosis caused by high fat diet (HF) feeding. The essential genes assessment, hepatic metabolic analysis and triglyceride-rich very low-density lipoprotein (VLDL-TG) secretion assays revealed a higher β-oxidation of fatty acids (FAs) but impaired VLDL-TG secretion in liver of DSS-treated mice. Disruption of the intestinal barrier by DSS promoted liver inflammation, which strongly suppressed hepatic VLDL-TG secretion and further aggravated HF-induced VLDL-TG secretion impairment through down-regulation of apolipoprotein B (APOB), hence promoting the storage of triglycerides (TG) in the liver. Inflammation induced by mixed proinflammatory cytokines or LPS obviously inhibited the expression of microsomal triglyceride transfer protein (MTP) and APOB expression and subsequently increased TG content via the suppression of HNF4α in mouse primary hepatocytes. In addition, the downregulation of MTP and APOB by proinflammatory cytokines was also rescued through activating Hnf4α by cortisol. Altogether, our results demonstrated that chronic inflammation exacerbated hepatic steatosis by inhibiting the secreting of hepatic VLDL-TG through HNF4α pathway, suggesting that restoring hepatic VLDL-TG secretion may be a novel strategy for treatment of NAFLD in IBD. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Ping Li, Xiu Chen, Minlei Dong, Jun Luo, Shuanghui Lu, Mingyang Chen, Yingqiong Zhang, Hui Zhou, Huidi Jiang. Gut inflammation exacerbates high-fat diet induced steatosis by suppressing VLDL-TG secretion through HNF4α pathway. Free radical biology & medicine. 2021 Aug 20;172:459-469

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PMID: 34186207

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