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USP29 alleviates the progression of MASLD by stabilizing ACSL5 through K48 deubiquitination

Sha Hu1, Zhouxiang Wang1, Kun Zhu1

  • 1Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, China.

Clinical and Molecular Hepatology
|October 2, 2024
PubMed
Abstract

Insights

Ubiquitin-specific protease 29 (USP29) protects against metabolic dysfunction-associated steatotic liver disease (MASLD) by stabilizing ACSL5 to enhance fatty acid oxidation. USP29 activation offers a potential therapeutic avenue for MASLD.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Biochemistry

Background:

  • Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern characterized by fat accumulation in the liver.
  • The role of Ubiquitin-specific protease 29 (USP29) in MASLD pathogenesis is currently unknown.
  • USP29 is implicated in other liver conditions like ischemia-reperfusion injury and hepatocellular carcinoma.

Purpose of the Study:

  • To investigate the role and underlying molecular mechanisms of USP29 in the progression of MASLD.
  • To determine if USP29 expression is altered in MASLD patients and animal models.

Main Methods:

  • Assessed USP29 expression in human and mouse liver samples from MASLD patients and models.
  • Utilized high-fat diet and high-fat/high-cholesterol diet-induced mouse models of MASLD.
  • Employed palmitic acid and oleic acid treatments in cultured hepatocytes to study USP29 function.
  • Investigated USP29 interaction with ACSL5 and its effect on ACSL5 degradation.

Main Results:

  • USP29 protein levels were significantly decreased in MASLD patients and mice.
  • USP29 deficiency exacerbated hepatic steatosis, inflammation, and fibrosis, while overexpression ameliorated these conditions.
  • USP29 stabilized ACSL5 by deubiquitination, promoting fatty acid beta-oxidation (FAO).
  • The protective effects of USP29 against MASLD were dependent on ACSL5.

Conclusions:

  • USP29 acts as a novel negative regulator of MASLD by enhancing FAO through ACSL5 stabilization.
  • The USP29-ACSL5 pathway presents a promising therapeutic target for treating MASLD.
Keywords:
ACSL5 protein, humanLipid metabolism disordersMetabolic dysfunction-associtaed steatotic liver diseaseUSP29 protein, human

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