A Mitochondrial VDAC1-Based Peptide Greatly Suppresses Steatosis and NASH-Associated Pathologies in a Mouse Model

Srinivas Pittala, Yakov Krelin, Yael Kuperman, Varda Shoshan-Barmatz

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Non-alcoholic steatosis and non-alcoholic steatohepatitis (NASH) are liver pathologies characterized by severe metabolic alterations due to fat accumulation that lead to liver damage, inflammation, and fibrosis. We demonstrate that the voltage-dependent anion channel 1 (VDAC1)-based peptide R-Tf-D-LP4 arrested steatosis and NASH progression, as produced by a high-fat diet (HFD-32) in a mouse model, and reversed liver pathology to a normal-like state. VDAC1, a multi-functional mitochondrial protein, regulates cellular metabolic and energetic functions and apoptosis and interacts with many proteins. R-Tf-D-LP4 treatment eliminated hepatocyte ballooning degeneration, inflammation, and liver fibrosis associated with steatosis, NASH, and hepatocarcinoma, and it restored liver pathology-associated enzyme and glucose levels. Peptide treatment affected carbohydrate and lipid metabolism, increasing the expression of enzymes and factors associated with fatty acid transport to mitochondria, enhancing β-oxidation and thermogenic processes, yet decreasing the expression of enzymes and regulators of fatty acid synthesis. The VDAC1-based peptide thus offers a promising therapeutic approach for steatosis and NASH.

Original languageEnglish
Pages (from-to)1848-1862
Number of pages15
JournalMolecular Therapy
Volume27
Issue number10
DOIs
StatePublished - 2 Oct 2019

Keywords

  • NAFLD
  • NASH
  • VDAC1
  • liver
  • metabolism
  • mitochondria
  • peptide
  • steatosis

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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