(The) role of TCF7L2 on hepatic lipid metabolism

Abstract

Nonalcoholic fatty liver disease (NAFLD) associated with type 2 diabetes more easily progresses toward severe forms of nonalcoholic steatohepatitis (NASH) and fibrosis, and the underlying mechanism is under active investigation. Transcription factor 7-like 2 (TCF7L2), the most significant type 2 diabetes susceptibility gene, is one of the factors that exerts the genetic signals associated with nonalcoholic fatty liver disease (NAFLD). However, the role of TCF7L2 deficiency in hepatic lipid metabolism is poorly defined. Here, we established the role of TCF7L2 in hepatic lipid metabolism. First, We found that TCF7L2 expression decreased in the liver samples of patients with NAFLD/NASH. Based on the major risk factors of NAFLD development, Liver-specific TCF7L2 knockout (Alb-Cre

TCF7L2f/f ) mice were subjected to a high-fat diet (HFD) providing fatty acids (FAs) and refeeding/high-carbohydrate diet (HCD) stimulating de novo lipogenesis. Under HFD conditions, Alb-Cre

TCF7L2f/f mice exhibited impaired glucose tolerance and insulin tolerance, but no significant changes in hepatic TG levels. On the other hand, under normal chow (NC)- and high-carbohydrate (HC)- refeeding for stimulating DNL, loss of hepatic TCF7L2 promoted expression of lipogenic genes and hepatic TG accumulation in a carbohydrate loading time- and amount- dependent manner. Indeed, the absence of hepatic TCF7L2 aggravated liver steatosis and elevated ALT levels by preferentially metabolizing HC than HF in 22 weeks of diet-induced NAFLD/NASH models. In addition, Alb-Cre

TCF7L2f/f mice fed a HCD for 22 weeks impaired glucose and insulin tolerance and impeded hepatic insulin signaling. In mice, TCF7L2 is a potential regulator of NAFLD associated with dietary carbohydrates and diabetes. Loss of hepatic TCF7L2 contributes to liver steatosis by preferentially metabolizing carbohydrates, which results from increased DNL. Our finding will provide a better understanding of NAFLD associated with dietary carbohydrates and diabetes.