Hepatic triglyceride (TAG) accumulation leads to the development of non-alcoholic fatty liver disease (NAFLD), which is strongly correlated with other metabolic diseases including obesity, insulin resistance and type II diabetes. While the TAG synthetic pathway has been well-researched, our knowledge of the TAG hydrolysis pathway, especially in the liver, is scant. The research project is aimed at understanding the role and mechanisms of hepatic adipose triglyceride lipase (ATGL) and its downstream lipid metabolites in mediating the development of NAFLD and insulin resistance. To elucidate the metabolic functions of hepatic ATGL, we employed adenovirus-mediated knockdown and overexpression in primary hepatocyte cultures and mouse models. We have shown that ATGL is a key TAG hydrolase in the liver that preferentially channels fatty acids (FAs) to mitochondrial β-oxidation, but does not affect VLDL synthesis and secretion. Additionally, ATGL positively regulates PPAR-α and its target gene expression to influence β-oxidation transcriptionally. Liver FA binding protein (LFABP), a major intracellular FA carrier, is not necessary for ATGL-regulated changes in the expression of PPAR-α and its target genes or for the shuttling of hydrolyzed FA to the mitochondria. Moreover, the PPAR-α agonist fenofibrate is unable to normalize the expression of PPAR-α target genes in ATGL knockdown mice, suggesting that ATGL regulates PPAR-α target gene expression in a LFABP- and ligand-independent mechanism. Interestingly, despite enhanced TAG content, mice lacking hepatic ATGL are actually more glucose tolerant without exhibiting impaired insulin signaling. ATGL knockdown also normalizes glucose intolerance in HF diet-induced obese mice. Hepatocytes isolated from mice receiving ATGL knockdown adenovirus display higher glucose oxidation and lower glucose production compared to control cells. Thus, hepatic ATGL knockdown enhances glucose tolerance by increasing hepatic glucose utilization, and uncouples impairments in insulin action from hepatic TAG accumulation. Taken together, hepatic ATGL is a major player in TAG catabolism and FA oxidation. Further investigation is warranted to understand the mechanisms through which ATGL mediates FA oxidation, PPAR-α activity and the uncoupling of hepatic TAG accumulation from impaired insulin signaling and insulin resistance.
University of Minnesota Ph.D. dissertation. June 2013. Major: Nutrition. Advisor: Dr. Douglas G. Mashek. 1 computer file (PDF); ix, 169 pages.
Ong, Kuok Teong.
The role of adipose triglyceride lipase in hepatic lipid metabolism, non-alcoholic fatty liver disease and insulin resistance.
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