| First Author | Yang X | Year | 2021 |
| Journal | Hepatology | Volume | 74 |
| Issue | 3 | Pages | 1319-1338 |
| PubMed ID | 33894019 | Mgi Jnum | J:332191 |
| Mgi Id | MGI:7411347 | Doi | 10.1002/hep.31863 |
| Citation | Yang X, et al. (2021) Hepatocyte SH3RF2 Deficiency Is a Key Aggravator for NAFLD. Hepatology 74(3):1319-1338 |
| abstractText | BACKGROUND AND AIMS: NAFLD has become the most common liver disease worldwide but lacks a well-established pharmacological therapy. Here, we aimed to investigate the role of an E3 ligase SH3 domain-containing ring finger 2 (SH3RF2) in NAFLD and to further explore the underlying mechanisms. METHODS AND RESULTS: In this study, we found that SH3RF2 was suppressed in the setting of NAFLD across mice, monkeys, and clinical individuals. Based on a genetic interruption model, we further demonstrated that hepatocyte SH3RF2 deficiency markedly deteriorates lipid accumulation in cultured hepatocytes and diet-induced NAFLD mice. Mechanistically, SH3RF2 directly binds to ATP citrate lyase, the primary enzyme promoting cytosolic acetyl-coenzyme A production, and promotes its K48-linked ubiquitination-dependent degradation. Consistently, acetyl-coenzyme A was significantly accumulated in Sh3rf2-knockout hepatocytes and livers compared with wild-type controls, leading to enhanced de novo lipogenesis, cholesterol production, and resultant lipid deposition. CONCLUSION: SH3RF2 depletion in hepatocytes is a critical aggravator for NAFLD progression and therefore represents a promising therapeutic target for related liver diseases. |
