The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation

Hepatology. 2017 Oct;66(4):1111-1124. doi: 10.1002/hep.29273. Epub 2017 Aug 26.


A sequence variation (I148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is strongly associated with fatty liver disease, but the underlying mechanism remains obscure. In this study, we used knock-in (KI) mice (Pnpla3148M/M ) to examine the mechanism responsible for accumulation of triglyceride (TG) and PNPLA3 in hepatic lipid droplets (LDs). No differences were found between Pnpla3148M/M and Pnpla3+/+ mice in hepatic TG synthesis, utilization, or secretion. These results are consistent with TG accumulation in the Pnpla3148M/M mice being caused by impaired TG mobilization from LDs. Sucrose feeding, which is required to elicit fatty liver in KI mice, led to a much larger and more persistent increase in PNPLA3 protein in the KI mice than in wild-type (WT) mice. Inhibition of the proteasome (bortezomib), but not macroautophagy (3-methyladenine), markedly increased PNPLA3 levels in WT mice, coincident with the appearance of ubiquitylated forms of the protein. Bortezomib did not increase PNPLA3 levels in Pnpla3148M/M mice, and only trace amounts of ubiquitylated PNPLA3 were seen in these animals.

Conclusion: These results are consistent with the notion that the 148M variant disrupts ubiquitylation and proteasomal degradation of PNPLA3, resulting in accumulation of PNPLA3-148M and impaired mobilization of TG from LDs. (Hepatology 2017;66:1111-1124).

MeSH terms

  • Adenine / analogs & derivatives
  • Animals
  • Caloric Restriction
  • Dietary Sucrose
  • Fatty Liver / genetics*
  • Fatty Liver / metabolism
  • Genetic Predisposition to Disease
  • Lipid Droplets / metabolism*
  • Lipid Metabolism
  • Mice, Transgenic
  • Oxidation-Reduction
  • Phospholipases A2, Calcium-Independent / genetics*
  • Phospholipases A2, Calcium-Independent / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Triglycerides / metabolism
  • Ubiquitination


  • Dietary Sucrose
  • Triglycerides
  • 3-methyladenine
  • PNPLA3 protein, mouse
  • Phospholipases A2, Calcium-Independent
  • Proteasome Endopeptidase Complex
  • Adenine