Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois.
Northwestern University, Chicago, Illinois.
Cell Mol Gastroenterol Hepatol. 2021;11(5):1291-1311. doi: 10.1016/j.jcmgh.2021.01.003. Epub 2021 Jan 11.
BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and alanine aminotransferase, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may activate peroxisome proliferator-activated receptor gamma (PPARγ) in hepatocytes and promote steatosis. Therefore, we assessed the role that hepatocyte-specific PPARγ plays in the development of NASH, and how it alters the therapeutic effects of TZD on the liver of mice with diet-induced NASH.
Hepatocyte-specific PPARγ expression was knocked out in adult mice before and after the development of NASH induced with a high fat, cholesterol, and fructose (HFCF) diet.
HFCF diet increased PPARγ expression in hepatocytes, and rosiglitazone further activated PPARγ in hepatocytes of HFCF-fed mice in vivo and in vitro. Hepatocyte-specific loss of PPARγ reduced the progression of HFCF-induced NASH in male mice and increased the benefits derived from the effects of TZD on extrahepatic tissues and non-parenchymal cells. RNAseq and metabolomics indicated that HFCF diet promoted inflammation and fibrogenesis in a hepatocyte PPARγ-dependent manner and was associated with dysregulation of hepatic metabolism. Specifically, hepatocyte-specific loss of PPARγ plays a positive role in the regulation of methionine metabolism, and that could reduce the progression of NASH.
Because of the negative effect of hepatocyte PPARγ in NASH, inhibition of mechanisms promoted by endogenous PPARγ in hepatocytes may represent a novel strategy that increases the efficiency of therapies for NAFLD.
非酒精性脂肪性肝炎（NASH）在 2 型糖尿病患者中较为常见，噻唑烷二酮类药物（TZD）被认为是 NASH 的潜在治疗药物。尽管 TZD 可增加胰岛素敏感性并部分减轻脂肪变性和丙氨酸氨基转移酶升高，但 TZD 对肝脏病理的疗效有限。事实上，TZD 可能在肝细胞中激活过氧化物酶体增殖物激活受体γ（PPARγ）并促进脂肪变性。因此，我们评估了肝细胞特异性 PPARγ在 NASH 发展中的作用，以及它如何改变 TZD 对饮食诱导的 NASH 小鼠肝脏的治疗作用。
在高脂肪、胆固醇和果糖（HFCF）饮食诱导的 NASH 发展之前和之后，敲除成年小鼠肝细胞中 PPARγ的表达。
HFCF 饮食增加了肝细胞中 PPARγ的表达，罗格列酮在体内和体外进一步激活了 HFCF 喂养小鼠肝细胞中的 PPARγ。肝细胞特异性 PPARγ缺失可降低雄性小鼠 HFCF 诱导的 NASH 的进展，并增加 TZD 对肝外组织和非实质细胞的治疗作用。RNAseq 和代谢组学表明，HFCF 饮食以肝细胞 PPARγ依赖的方式促进炎症和纤维化，并与肝脏代谢失调有关。具体而言，肝细胞特异性 PPARγ缺失在调控蛋氨酸代谢方面发挥了积极作用，这可能会减缓 NASH 的进展。
由于肝细胞 PPARγ在 NASH 中的负性作用，抑制肝细胞中内源性 PPARγ促进的机制可能代表一种提高非酒精性脂肪性肝病治疗效率的新策略。
