Obesity is associated with nonalcoholic fatty liver disease (NAFLD). NAFLD is a risk factor for insulin resistance and cardiovascular diseases, and leads to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver failure. Hepatic steatosis is believed to be """"""""the first hit"""""""", and """"""""the second hit"""""""" (e.g. oxidative, ER and oxidative stress) is aso required for NAFLD/NASH progression. However, the interplay of the first and second hits and the underlying mechanism of NAFLD/NASH progression remain unclear. In the preliminary study, we identified Snail2 as a novel regulator of lipid metabolism that is required for NAFLD in obesity. Snail2 is a transcriptional regulator believed to promote epithelial-to-mesenchymal transition (EMT) in development and cancer metastasis. It may also regulate proliferation and apoptosis in some cell types;however, its metabolic function has not been explored prior to this work. We show that the expression of hepatic Snail2 markedly increases in obesity. Genetic deletion of Snail2 prevents NAFLD, reduces liver oxidative, ER, and inflammatory stress, and improves insulin resistance and glucose intolerance in mice with either dietary or genetic obesity. Snail2 appears to perform dual actions, repressing the genes involved in fatty acid oxidation and activating the genes involved in lipid synthesis and uptake. In the current study, we will extend these observations to firmly establish the essential role of hepatic Snail2 in NAFLD progression and insulin resistance by generating and characterizing hepatocyte-specific Snail2 knockout or overexpressing mice. We will determine whether metabolic, oxidative, ER, and inflammatory stress increase the levels (via transcription and stability) and activity (via posttranslational modifications) of hepatic Snail2, which in turn promotes steatosis by increasing lipid synthesis and lipid uptake and decreasing oxidation. We will determine whether hepatic Snail2 connects the first and the second hits, and forms a hepatocellular stress-Snail2 vicious cycle that drives NAFLD progression in obesity. We will elucidate the mechanism by which hepatic Snail2 activates or represses the genes that control lipid synthesis, lipid uptake, and oxidation, and test the hypothesis that hepatic Snail2 genetically reprograms lipid pathways in the setting of obesity. The impact of this study lies in establishing a novel metabolic function of hepatic Snail2 and testing the novel concept that the hepatocellular stress-Snail2 vicious cycle drives NAFLD progression. The outcome is expected to lead to new therapies for NAFLD by targeting hepatic Snail2.
The prevalence of obesity is increasing rapidly. Obesity is associated with nonalcoholic fatty liver diseases (NAFLD). NAFLD leads to nonalcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma, and type 2 diabetes. Unfortunately, the underlying mechanism of obesity-induced NAFLD is unclear, which limits our ability to treat these diseases. In this study, we will establish a novel concept that a hepatocellular stress- Snail2 vicious cycle drives NAFLD progression. Thus, the outcome is expected to lead to a new treatment for NAFLD, NASH, cirrhosis, and type 2 diabetes by breaking this cycle.
|Jiang, Lin; Su, Haoran; Keogh, Julia M et al. (2018) Neural deletion of Sh2b1 results in brain growth retardation and reactive aggression. FASEB J 32:1830-1840|
|Liu, Yan; Jiang, Lin; Sun, Chengxin et al. (2018) Insulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis. Nat Commun 9:2751|
|Rui, Liangyou (2017) Brown and Beige Adipose Tissues in Health and Disease. Compr Physiol 7:1281-1306|
|Shen, Hong; Sheng, Liang; Xiong, Yi et al. (2017) Thymic NF-?B-inducing kinase regulates CD4+ T cell-elicited liver injury and fibrosis in mice. J Hepatol 67:100-109|
|Liu, Yan; Sheng, Liang; Xiong, Yi et al. (2017) Liver NF-?B-Inducing Kinase Promotes Liver Steatosis and Glucose Counterregulation in Male Mice With Obesity. Endocrinology 158:1207-1216|
|Sun, Chengxin; Jiang, Lin; Liu, Yan et al. (2016) Adipose Snail1 Regulates Lipolysis and Lipid Partitioning by Suppressing Adipose Triacylglycerol Lipase Expression. Cell Rep 17:2015-2027|
|Chen, Zheng; Canet, Mark J; Sheng, Liang et al. (2015) Hepatocyte TRAF3 promotes insulin resistance and type 2 diabetes in mice with obesity. Mol Metab 4:951-60|
|Jiang, Bijie; Shen, Hong; Chen, Zheng et al. (2015) Carboxyl terminus of HSC70-interacting protein (CHIP) down-regulates NF-?B-inducing kinase (NIK) and suppresses NIK-induced liver injury. J Biol Chem 290:11704-14|
|Chen, Zheng; Shen, Hong; Sun, Chengxin et al. (2015) Myeloid cell TRAF3 promotes metabolic inflammation, insulin resistance, and hepatic steatosis in obesity. Am J Physiol Endocrinol Metab 308:E460-9|
|Rui, Liangyou (2014) SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes 5:511-26|
Showing the most recent 10 out of 19 publications