| First Author | Pan X | Year | 2024 |
| Journal | Metabolism | Volume | 155 |
| Pages | 155909 | PubMed ID | 38582490 |
| Mgi Jnum | J:347881 | Mgi Id | MGI:7626136 |
| Doi | 10.1016/j.metabol.2024.155909 | Citation | Pan X, et al. (2024) Kruppel-like factor 10 protects against metabolic dysfunction-associated steatohepatitis by regulating HNF4alpha-mediated metabolic pathways. Metabolism 155:155909 |
| abstractText | BACKGROUND: Kruppel-like factor 10 (KLF10), a zinc finger transcription factor, plays a pivotal role in modulating TGF-beta-mediated cellular processes such as growth, apoptosis, and differentiation. Recent studies have implicated KLF10 in regulating lipid metabolism and glucose homeostasis. This study aimed to elucidate the precise role of hepatic KLF10 in developing metabolic dysfunction-associated steatohepatitis (MASH) in diet-induced obese mice. METHODS: We investigated hepatic KLF10 expression under metabolic stress and the effects of overexpression or ablation of hepatic KLF10 on MASH development and lipidemia. We also determined whether hepatocyte nuclear factor 4alpha (HNF4alpha) mediated the metabolic effects of KLF10. RESULTS: Hepatic KLF10 was downregulated in MASH patients and genetically or diet-induced obese mice. AAV8-mediated overexpression of KLF10 in hepatocytes prevented Western diet-induced hypercholesterolemia and steatohepatitis, whereas inactivation of hepatocyte KLF10 aggravated Western diet-induced steatohepatitis. Mechanistically, KLF10 reduced hepatic triglyceride and free fatty acid levels by inducing lipolysis and fatty acid oxidation and inhibiting lipogenesis, and reducing hepatic cholesterol levels by promoting bile acid synthesis. KLF10 highly induced HNF4alpha expression by directly binding to its promoter. The beneficial effect of KLF10 on MASH development was abolished in mice lacking hepatocyte HNF4alpha. In addition, the inactivation of KLF10 in hepatic stellate cells exacerbated Western diet-induced liver fibrosis by activating the TGF-beta/SMAD2/3 pathway. CONCLUSIONS: Our data collectively suggest that the transcription factor KLF10 plays a hepatoprotective role in MASH development by inducing HNF4alpha. Targeting hepatic KLF10 may offer a promising strategy for treating MASH. |
