Role of adipose triglyceride lipase in hepatic lipid homeostasis and lipotoxicity in alcohol-related liver disease
- UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
- Tianjiao Li (Creator)
- Institution
- The University of North Carolina at Greensboro (UNCG )
- Web Site: http://library.uncg.edu/
- Advisor
- Zhanxiang Zhou
Abstract: Alcohol-related liver disease (ALD) is a significant contributor to the liver disease burden worldwide. Hepatic steatosis is the earliest and most common clinical manifestation of ALD and is characterized by excessive triglyceride (TG)-enriched lipid droplet (LD) accumulation in the liver. Studies have shown that the activity of adipose triglyceride lipase (ATGL), the rate limiting enzyme of TG hydrolysis, is negatively related to hepatic LD content; however, it is unclear whether ATGL plays a role in the pathogenesis of ALD. While a previous study reported that patients with non-alcoholic fatty liver disease showed reduced hepatic ATGL expression, it remains unclear how alcohol affects hepatic ATGL expression and what role ATGL plays in hepatic lipid metabolism in ALD. Although much effort has been made, the role of ATGL in hepatic lipotoxicity and inflammation has not been established. Therefore, a mouse model with hepatocyte-specific deletion of ATGL was generated and subjected to chronic alcohol feeding for 8 wk. Data presented in this dissertation suggest that alcohol induces hepatic ATGL expression, accumulation of TGs and free fatty acids (FFAs), and liver injury. Hepatocyte-specific ATGL deletion in mice further exacerbated alcohol-induced hepatic steatosis, inflammation, as well as fibrosis. Moreover, hepatocyte-specific ATGL deletion suppressed TG-enriched very-low-density lipoprotein (VLDL) secretion through impairing long-chain acyl-CoA synthetase 5 (ACSL5)-mediated fatty acid oxidation and subsequent incorporation of FFAs into TGs by diacylglycerol O-acyltransferase 1 (DGAT1). In addition, we found that hepatocyte-specific ATGL deletion aggravated alcohol-induced liver inflammation by upregulating chemokine CXCL1 and cytokine LCN2 and promoting subsequent neutrophil infiltration. Given the sophisticated structure of the liver and the properties of transmission electron microscope (TEM) in directly visualizing liver morphology under high magnification, we utilized this unique technique to evaluate the subcellular and functional changes in various cells of the liver of mice. We observed that alcohol intoxication perturbs the normal structure and morphology of mouse hepatocytes, such as reduced number of mitochondria and glycogen storage, LD accumulation, ER dilation and fragmentation, and the accumulation of autolysosomes in the cytoplasm. We further found that hepatocyte ATGL deficiency aggravated alcohol-caused structural and morphological changes in hepatocytes, Kupffer cells, hepatic stellate cells, and cholangiocytes in mice. Lipotoxicity and translocation of gut-derived endotoxin (lipopolysaccharides, LPS) to the liver have both been reported to be involved in ER stress-mediated hepatic cell death. In the last set of experiments, in vitro cell culture studies were conducted using AML12 cells. This study showed that TG/LD accumulation and LPS stimulation synergistically induced cell death, stimulated ER stress, and upregulated CXCL1 and LCN2 expression via I?B-? activation in hepatocytes. Collectively, data presented in this dissertation revealed the molecular mechanisms by which hepatocyte ATGL deficiency exacerbated alcohol-induced hepatic steatosis, hepatocyte death, and liver inflammation in the pathogenesis of ALD, which may advance the development and optimization of innovative diagnostic and therapeutic strategies targeting lipotoxicity for ALD treatment.
Role of adipose triglyceride lipase in hepatic lipid homeostasis and lipotoxicity in alcohol-related liver disease
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Created on 5/1/2022
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Additional Information
- Publication
- Dissertation
- Language: English
- Date: 2022
- Keywords
- Adipose Triglyceride Lipase, Alcohol-related liver disease, Hepatic Lipid Homeostasis, Lipid Metabolism, Lipotoxicity
- Subjects
- Alcoholic liver diseases
- Hepatotoxicology
- Lipids $x Metabolism