Non-alcoholic fatty liver disease (NAFLD), defined by lipid droplet (LD) accumulation, is a prevalent disorder that is involved in the etiology of numerous metabolic diseases including obesity, diabetes and cardiovascular disease. Despite the importance of TAG metabolism and the advancements into our understanding of the TAG synthetic pathway, the mechanisms regulating hepatic TAG hydrolysis and their effects on disease etiology are unknown. The objective of this administrative supplement is to characterize how the dynamic hepatic LD and nuclear lipidomes change in response to metabolic stimuli such as high fat feeding, ATGL-catalyzed lipolysis and B-adrenergic signaling. We hypothesis and ATGL uniquely alters LD and nuclear lipidomes and that specific lipid species generated by ATGL contribute to Sirt1 regulation and the downstream effects on cell signaling. We base this hypothesis on Preliminary Studies from our laboratory showing that ATGL induces Sirt1 activity to control PGC1-A/PPAR-a signaling, mediates the effects of B-adrenergic signaling on Sirt1/PGC1- a/PPAR-a signaling, and induces mitochondrial biogenesis and fatty acid oxidation in a Sirt1 dependent manner. The rationale for the proposed research is that identifying changes in LD and nuclear lipidomes will greatly advance our understanding of the contribution of these organelles and their lipidomes in disease etiology and may help identify the mechanism through which ATGL regulates Sirt1. The hypothesis will be tested using two specific aims: 1) to determine how high fat feeding alters the hepatic LD and nuclear lipidome and the importance of ATGL in altering these changes and 2) to determine how LD and nuclear lipidomes change in response to B-adrenergic signaling and the role of ATGL/lipolysis in mediating these effects. Under the first aim, we will perform lipidomic profiling of hepatic nuclei and LDs in mice treated with control or ATGL shRNA fed control or high fat diets for 3 months.
The second aim will characterize the effects of B-adrenergic signaling and chronic (shRNA) or acute (chemical) inhibition of ATGL on the LD and nuclear lipidomes of primary mouse hepatocytes. These studies are innovative because they will employ the powerful technical platform of lipidomic profiling to the understudied area of LD biology and organelle-specific lipidomics. The proposes work is significant because it will further our understanding into the link between LD accumulation (i.e. steatosis), energy signaling pathways and the etiology of NAFLD and Type 2 Diabetes.

Public Health Relevance

The proposed research will advance our understanding into the complex etiology of non-alcoholic fatty liver disease and its relationship with numerous other diseases including Type 2 Diabetes. In addition, the data gleaned from these studies will further define the complex role of lipid metabolism in mediating cellular events to prevent or treat metabolic diseases and, thus, will have a direct effect on human health.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Laughlin, Maren R
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University of Minnesota Twin Cities
Schools of Earth Sciences/Natur
United States
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Khan, Salmaan Ahmed; Sathyanarayan, Aishwarya; Mashek, Mara T et al. (2015) ATGL-catalyzed lipolysis regulates SIRT1 to control PGC-1α/PPAR-α signaling. Diabetes 64:418-26
Mashek, Douglas G; Khan, Salmaan A; Sathyanarayan, Aishwarya et al. (2015) Hepatic lipid droplet biology: Getting to the root of fatty liver. Hepatology 62:964-7
Ong, Kuok Teong; Mashek, Mara T; Davidson, Nicholas O et al. (2014) Hepatic ATGL mediates PPAR-α signaling and fatty acid channeling through an L-FABP independent mechanism. J Lipid Res 55:808-15
Ong, Kuok Teong; Mashek, Mara T; Bu, So Young et al. (2013) Hepatic ATGL knockdown uncouples glucose intolerance from liver TAG accumulation. FASEB J 27:313-21
Mashek, Douglas G (2013) Hepatic fatty acid trafficking: multiple forks in the road. Adv Nutr 4:697-710
Ong, Kuok Teong; Mashek, Mara T; Bu, So Young et al. (2011) Adipose triglyceride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning. Hepatology 53:116-26
Coleman, Rosalind A; Mashek, Douglas G (2011) Mammalian triacylglycerol metabolism: synthesis, lipolysis, and signaling. Chem Rev 111:6359-86