A functional interaction between Hippo‐YAP signalling and SREBPs mediates hepatic steatosis in diabetic mice

• Published in: Journal of cellular and molecular medicine 2019-05, Vol.23 (5), p.3616-3628
• Main Authors: Shu, Zhiping, Gao, Yuan, Zhang, Guopeng, Zhou, Yu, Cao, Jing, Wan, Dongyi, Zhu, Xiaohua, Xiong, Wenqian
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Diabetes Mellitus, Experimental - etiology; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diet, High-Fat - adverse effects; Fatty Acid Synthases - genetics; Fatty Acid Synthases - metabolism; Fatty Liver - genetics; Fatty Liver - metabolism; hepatic steatosis; Hepatocytes - metabolism; Hippo signalling; Lipogenesis - genetics; Male; Mice, Inbred C57BL; Mice, Knockout; Original; Promoter Regions, Genetic - genetics; Protein Binding; Protein-Serine-Threonine Kinases - metabolism; Signal Transduction - genetics; SREBPs; Sterol Regulatory Element Binding Protein 1 - metabolism; Sterol Regulatory Element Binding Protein 2 - metabolism; transcriptional activity; YAP
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.14262

The Hippo pathway is an evolutionarily conserved regulator of organ size and tumorigenesis that negatively regulates cell growth and survival. Whether the Hippo pathway regulates cell metabolism is unknown. Here, we report that in the nucleus of hepatocytes, Yes‐associated protein(YAP)—the terminal effector of the Hippo pathway—directly interacts with sterol regulatory element binding proteins (SREBP‐1c and SREBP‐2) on the promoters of the fatty acid synthase (FAS) and 30‐hydroxylmethyl glutaryl coenzyme A reductase (HMGCR), thereby stimulating their transcription and promoting hepatocyte lipogenesis and cholesterol synthesis. In diet‐induced diabetic mice, either Lats1 overexpression or YAP knockdown protects against hepatic steatosis and hyperlipidaemia through suppression of the interaction between YAP and SREBP‐1c/SREBP‐2. These results suggest that YAP is a nuclear co‐factor of SREBPs and that the Hippo pathway negatively affects hepatocyte lipogenesis by inhibiting the function of YAP‐SREBP complexes.