| First Author | BasuRay S | Year | 2017 |
| Journal | Hepatology | Volume | 66 |
| Issue | 4 | Pages | 1111-1124 |
| PubMed ID | 28520213 | Mgi Jnum | J:273935 |
| Mgi Id | MGI:6282944 | Doi | 10.1002/hep.29273 |
| Citation | BasuRay S, et al. (2017) The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 66(4):1111-1124 |
| abstractText | 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 (Pnpla3(148M/M) ) to examine the mechanism responsible for accumulation of triglyceride (TG) and PNPLA3 in hepatic lipid droplets (LDs). No differences were found between Pnpla3(148M/M) and Pnpla3(+/+) mice in hepatic TG synthesis, utilization, or secretion. These results are consistent with TG accumulation in the Pnpla3(148M/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 Pnpla3(148M/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). |
