Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality in the United States and worldwide. Unfortunately, there is currently no FDA approved medication for any stage of ALD. Advancing our knowledge on the pathophysiologic mechanisms of ALD will certainly pave the way to development of therapeutic interventions. Alcoholic steatosis is the earliest pathological change in the progression of ALD, and it is routinely assessed by histological and/or histochemical methods. However, these morphological methods can only demonstrate lipid droplets which contain neutral lipids with triglyceride as the major component. Although great efforts have been paid to understand the mechanisms by which alcohol abuse induces hepatic accumulation of lipid droplets, particularly triglyceride, increasing evidence suggest that free fatty acid (FFA) rather than triglyceride generates lipotoxicity. Accumulation of FFA in the liver has been documented in ALD, but the mechanisms of how alcohol abuse induces hepatic FFA accumulation and how FFA induces lipotoxicity have not been well defined. Lipid metabolism in the liver involves multiple metabolic pathways including de novo lipogenesis, fatty acid oxidation, lipid uptake and lipid export. In the past granting period, we have shown that alcohol abuse causes hepatic lipid accumulation by increasing fatty acid influx and reducing fatty acid oxidation as well as lipid export. White adipose tissue (WAT) as an energy buffering station communicates with liver by depositing liver-secreted triglyceride and releasing FFA to the liver. Alcohol impairs WAT functions in lipid storage and thereby leads to excessive FA release and hepatic influx. We found that lipin1, a critical enzyme in triglyceride synthesis, was dramatically reduced in the WAT after alcohol exposure, suggesting that lipid1 deficiency could be an important mechanism underlying alcohol-induced excessive FA release from the WAT to the liver. The hepatocytes control intracellular FFA level via two major mechanisms, assembling FFA into triglyceride and FA oxidation. Suppression of FA oxidation is likely an important mechanism underlying FFA accumulation in ALD. Accumulation of FFA in cells generates lipotoxicity. Our preliminary data showed that FFA induces ER stress and cell death dependent on activation of aryl hydrocarbon receptor (AhR). AhR is a xenobiotic nuclear factor, and activation of AhR is known to induce cell death. Our findings in the past granting period strongly support a novel concept that hepatic accumulation of FFA produces lipotoxicity via activating AhR signaling pathway. This project aims at understanding the mechanisms of how chronic alcohol exposure induces hepatic accumulation of FFA and how FFA induces cytotoxic signaling in the liver. Our overall hypothesis is that increased hepatic FA influx and impaired FA clearance account for alcohol-induced hepatic accumulation of FFA, and activation of AhR signaling pathway by FFA represents a novel mechanism underlying FFA lipotoxicity.

Public Health Relevance

Alcoholic liver disease is a leading cause of morbidity and mortality worldwide, but effective therapies are currently lack. This project is to investigate the mechanisms of how alcohol abuse induces hepatic accumulation of free fatty acid and how free fatty acid causes cell death. The goal of this project is to explore molecular targets for development of therapeutic interventions.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Gao, Peter
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University of North Carolina Greensboro
Sch Allied Health Professions
United States
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Zhang, Wenliang; Zhong, Wei; Sun, Qian et al. (2018) Adipose-specific lipin1 overexpression in mice protects against alcohol-induced liver injury. Sci Rep 8:408
Hao, Liuyi; Sun, Qian; Zhong, Wei et al. (2018) Mitochondria-targeted ubiquinone (MitoQ) enhances acetaldehyde clearance by reversing alcohol-induced posttranslational modification of aldehyde dehydrogenase 2: A molecular mechanism of protection against alcoholic liver disease. Redox Biol 14:626-636
Chen, Guan-Yuan; Zhong, Wei; Zhou, Zhanxiang et al. (2018) Simultaneous determination of tryptophan and its 31 catabolites in mouse tissues by polarity switching UHPLC-SRM-MS. Anal Chim Acta 1037:200-210
Zhang, Wenliang; Zhong, Wei; Sun, Qian et al. (2017) Hepatic overproduction of 13-HODE due to ALOX15 upregulation contributes to alcohol-induced liver injury in mice. Sci Rep 7:8976
Zhou, Zhanxiang; Zhong, Wei (2017) Targeting the gut barrier for the treatment of alcoholic liver disease. Liver Res 1:197-207
Sun, Qian; Zhang, Wenliang; Zhong, Wei et al. (2017) Pharmacological inhibition of NOX4 ameliorates alcohol-induced liver injury in mice through improving oxidative stress and mitochondrial function. Biochim Biophys Acta Gen Subj 1861:2912-2921
Sun, Qian; Zhong, Wei; Zhang, Wenliang et al. (2016) Defect of mitochondrial respiratory chain is a mechanism of ROS overproduction in a rat model of alcoholic liver disease: role of zinc deficiency. Am J Physiol Gastrointest Liver Physiol 310:G205-14
Sun, Qian; Zhang, Wenliang; Zhong, Wei et al. (2016) Dietary Fisetin Supplementation Protects Against Alcohol-Induced Liver Injury in Mice. Alcohol Clin Exp Res 40:2076-2084
Zhang, Wenliang; Sun, Qian; Zhong, Wei et al. (2016) Hepatic Peroxisome Proliferator-Activated Receptor Gamma Signaling Contributes to Alcohol-Induced Hepatic Steatosis and Inflammation in Mice. Alcohol Clin Exp Res 40:988-99
Dong, Daoyin; Zhong, Wei; Sun, Qian et al. (2016) Oxidative products from alcohol metabolism differentially modulate pro-inflammatory cytokine expression in Kupffer cells and hepatocytes. Cytokine 85:109-19

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