Affiliation:
1. State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi'an 710032 China
2. Department of Gastroenterology The Second Medical Center of PLA General Hospital Beijing 100853 China
3. Key Laboratory of Resource Biology and Biotechnology in Western China Ministry of Education, School of Medicine, Northwest University Xi'an 710069 China
Abstract
AbstractBackground and AimsNonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Aberrant lipid metabolism and accumulation of extracellular matrix proteins are hallmarks of the disease, but the underlying mechanisms are largely unknown. This study aims to elucidate the key role of sine oculis homeobox homologue 1 (SIX1) in the development of NAFLD.MethodsAlb‐Cre mice were administered the AAV9 vector for SIX1 liver‐specific overexpression or knockdown. Metabolic disorders, hepatic steatosis, and inflammation were monitored in mice fed with HFHC or MCD diet. High throughput CUT&Tag analysis was employed to investigate the mechanism of SIX1 in diet‐induced steatohepatitis.ResultsHere, we found increased SIX1 expression in the livers of NAFLD patients and animal models. Liver‐specific overexpression of SIX1 using adeno‐associated virus serotype 9 (AAV9) provoked more severe inflammation, metabolic disorders, and hepatic steatosis in the HFHC or MCD‐induced mice model. Mechanistically, we demonstrated that SIX1 directly activated the expression of liver X receptor α (LXRα) and liver X receptor β (LXRβ), thus inducing de novo lipogenesis (DNL). In addition, our results also illustrated a critical role of SIX1 in regulating the TGF‐β pathway by increasing the levels of type I and II TGF‐β receptor (TGFβRI/TGFβRII) in hepatic stellate cells (HSCs). Finally, we found that liver‐specific SIX1 deficiency could ameliorate diet‐induced NAFLD pathogenesis.ConclusionOur findings suggest a detrimental function of SIX1 in the progression of NAFLD. The direct regulation of LXRα/β and TGF‐β signalling by SIX1 provides a new regulatory mechanism in hepatic steatosis and fibrosis.
Funder
National Natural Science Foundation of China