Alcoholic fatty liver is considered as the earliest pathological alteration of progression in alcoholic liver disease (ALD) from hepatic steatosis to hepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Hepatic reverse transport of free fatty acids (FFAs) derived from adipose hyperlipolysis resulting from alcohol ingestion plays a critical role in fatty liver formation. However, the mechanisms by which alcohol regulates adipose tissue lipolysis are unclear. Recently, fibroblast growth factor 21 (FGF21) has emerged as a hepatic regulatory factor that acts on multiple targets, including the liver itself in an autocrine fashion, and importantly on white adipose tissue to regulate lipid homeostasis. We have found that FGF21 plays a critical role in alcohol-induced adipose lipolysis and in hepatic fat accumulation in animal models of ALD, and circulating FGF21 levels are significantly increased in patients with ALD and in experimental animal models. However, how FGF21 regulates adipose tissue lipolysis during alcohol exposure is not known.
The aims of this project are to investigate the role of FGF21 in adipose tissue lipolysis in response to alcohol exposure to improve our understanding of the molecular mechanisms in the regulation and action of this hormone in ALD, and to assess the therapeutic potential in alcohol-induced fatty liver formation. To achieve this goal, we will carry out the following specific aims.
In aim 1 we will determine whether FGF21 plays a stimulatory role in adipose tissue lipolysis and the underlying mechanisms associated with hormone sensitive lipase and perilipin pathway during alcohol exposure using FGF21 knockout and transgenic overexpression mouse models. In the second aim, we will test our hypothesis that adipose tissue specific disruption of FGF21 decreases FFA release and hepatic uptake and attenuates alcohol-induced fatty liver formation using adipose selective ?-klotho knockout mice.
Alcoholic fatty liver is considered as the earliest pathological alteration of progression in alcoholic liver disease (ALD) from hepatic steatosis to hepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Using animal models, we will investigate the role of FGF21 in response to alcohol exposure to improve our understanding of the molecular mechanisms in the regulation and action of this hormone in ALD, and to assess the therapeutic potential in alcohol- induced fatty liver formation.
|Shao, Tuo; Zhao, Cuiqing; Li, Fengyuan et al. (2018) Intestinal HIF-1? deletion exacerbates alcoholic liver disease by inducing intestinal dysbiosis and barrier dysfunction. J Hepatol 69:886-895|
|Yuan, Fuqiang; Chen, Xiaopan; Liu, Jie et al. (2018) Sulforaphane restores acetyl-histone H3 binding to Bcl-2 promoter and prevents apoptosis in ethanol-exposed neural crest cells and mouse embryos. Exp Neurol 300:60-66|
|Wu, Guicheng; Liu, Yanlong; Liu, Yunhuan et al. (2018) FGF 21 deficiency slows gastric emptying and reduces initial blood alcohol concentration in mice exposed to acute alcohol in fasting state. Biochem Biophys Res Commun 497:46-50|
|Kong, Xiaoxia; Yang, Ying; Ren, Li et al. (2017) Activation of autophagy attenuates EtOH-LPS-induced hepatic steatosis and injury through MD2 associated TLR4 signaling. Sci Rep 7:9292|
|Yuan, Fuqiang; Chen, Xiaopan; Liu, Jie et al. (2017) Up-regulation of Siah1 by ethanol triggers apoptosis in neural crest cells through p38 MAPK-mediated activation of p53 signaling pathway. Arch Toxicol 91:775-784|
|Liu, Liming; Zhao, Cuiqing; Yang, Ying et al. (2017) Fibroblast Growth Factor 21 Deficiency Attenuates Experimental Colitis-Induced Adipose Tissue Lipolysis. Gastroenterol Res Pract 2017:3089378|
|Yu, Jinsheng; Marsh, Sharon; Hu, Junbo et al. (2016) The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background. Gastroenterol Res Pract 2016:2862173|
|Li, Fengyuan; Duan, Kangmin; Wang, Cuiling et al. (2016) Probiotics and Alcoholic Liver Disease: Treatment and Potential Mechanisms. Gastroenterol Res Pract 2016:5491465|
|Yu, Jinsheng; Marsh, Sharon; Hu, Junbo et al. (2016) Gut Microbiota and Metagenomic Advancement in Digestive Disease. Gastroenterol Res Pract 2016:4703406|
|Deng, Zhong-Bin; Zhuang, Xiaoying; Ju, Songwen et al. (2016) Correction: Exosome-like Nanoparticles from Intestinal Mucosal Cells Carry Prostaglandin E2 and Suppress Activation of Liver NKT Cells. J Immunol 196:4832|
Showing the most recent 10 out of 26 publications