Sirtuin3 promotes the degradation of hepatic Z alpha-1 antitrypsin through lipophagy

Hepatol Commun. 2024 Jan 29;8(2):e0370. doi: 10.1097/HC9.0000000000000370. eCollection 2024 Feb 1.


Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by misfolding and accumulation of mutant alpha-1 antitrypsin (ZAAT) in the endoplasmic reticulum of hepatocytes. Hepatic ZAAT aggregates acquire a toxic gain-of-function that impacts the endoplasmic reticulum which is theorized to cause liver disease in individuals with AATD who present asymptomatic until late-stage cirrhosis. Currently, there is no treatment for AATD-mediated liver disease except liver transplantation. In our study of mitochondrial RNA, we identified that Sirtuin3 (SIRT3) plays a role in the hepatic phenotype of AATD.

Methods: Utilizing RNA and protein analysis in an in vitro AATD model, we investigated the role of SIRT3 in the pathophysiology of AATD-mediated liver disease while also characterizing our novel, transgenic AATD mouse model.

Results: We show lower expression of SIRT3 in ZAAT-expressing hepatocytes. In contrast, the overexpression of SIRT3 increases hepatic ZAAT degradation. ZAAT degradation mediated by SIRT3 appeared independent of proteasomal degradation and regular autophagy pathways. We observed that ZAAT-expressing hepatocytes have aberrant accumulation of lipid droplets, with ZAAT polymers localizing on the lipid droplet surface in a direct interaction with Perilipin2, which coats intracellular lipid droplets. SIRT3 overexpression also induced the degradation of lipid droplets in ZAAT-expressing hepatocytes. We observed that SIRT3 overexpression induces lipophagy by enhancing the interaction of Perilipin2 with HSC70. ZAAT polymers then degrade as a consequence of the mobilization of lipids through this process.

Conclusions: In this context, SIRT3 activation may eliminate the hepatic toxic gain-of-function associated with the polymerization of ZAAT, providing a rationale for a potential novel therapeutic approach to the treatment of AATD-mediated liver disease.

MeSH terms

  • Animals
  • Autophagy / genetics
  • Humans
  • Mice
  • Mice, Transgenic
  • Polymers
  • Sirtuin 3* / genetics
  • alpha 1-Antitrypsin Deficiency* / complications
  • alpha 1-Antitrypsin Deficiency* / genetics
  • alpha 1-Antitrypsin Deficiency* / metabolism
  • alpha 1-Antitrypsin* / genetics
  • alpha 1-Antitrypsin* / metabolism


  • Polymers
  • Sirtuin 3
  • alpha 1-Antitrypsin