PSA controls hepatic lipid metabolism by regulating the NRF2 signaling pathway

J Mol Cell Biol. 2021 Oct 21;13(7):527-539. doi: 10.1093/jmcb/mjab033.

Abstract

The activity of proteinase is reported to correlate with the development and progression of nonalcoholic fatty liver disease (NAFLD). Puromycin-sensitive aminopeptidase (PSA/NPEPPS) is an integral nontransmembrane enzyme that functions to catalyze the cleavage of amino acids near the N-terminus of polypeptides. A previous study suggested that this enzyme acts as a regulator of neuropeptide activity; however, the metabolic function of this enzyme in the liver has not been explored. Here, we identified the novel role of PSA in hepatic lipid metabolism. Specifically, PSA expression was lower in fatty livers from NAFLD patients and mice (HFD, ob/ob, and db/db). PSA knockdown in cultured hepatocytes exacerbated diet-induced triglyceride accumulation through enhanced lipogenesis and attenuated fatty acid β-oxidation. Moreover, PSA mediated activation of the master regulator of antioxidant response, nuclear factor erythroid 2-related factor 2 (NRF2), by stabilizing NRF2 protein expression, which further induced downstream antioxidant enzymes to protect the liver from oxidative stress and lipid overload. Accordingly, liver-specific PSA overexpression attenuated hepatic lipid accumulation and steatosis in ob/ob mice. Furthermore, in human liver tissue samples, decreased PSA expression correlated with the progression of NAFLD. Overall, our findings suggest that PSA is a pivotal regulator of hepatic lipid metabolism and its antioxidant function occurs by suppressing NRF2 ubiquitination. Moreover, PSA may be a potential biomarker and therapeutic target for treating NAFLD.

Keywords: NAFLD; NRF2; PSA; fatty acid β-oxidation; lipogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / genetics
  • Aminopeptidases / metabolism*
  • Animals
  • Antioxidants / metabolism*
  • Cell Line
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Gene Knockdown Techniques
  • Hepatocytes / metabolism
  • Humans
  • Lipid Metabolism / genetics*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Oxidative Stress / genetics
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / genetics*
  • Transfection
  • Triglycerides / metabolism

Substances

  • Antioxidants
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Reactive Oxygen Species
  • Triglycerides
  • Aminopeptidases
  • enkephalin degrading enzyme
  • Metalloendopeptidases
  • NPEPPS protein, human