Non-alcoholic fatty liver disease (NAFLD) and the progressive non-alcoholic steatohepatitis (NASH) are often associated with obesity, insulin resistance and coronary artery diseases. Most studies on hepatic steatosis have focused on enzymes involved in de novo lipogenesis. However, emerging data also point to critical contributions of proteins regulating intrahepatic lipolysis, including the key triglyceride hydrolae ATGL (adipose triglyceride lipase) along with its coactivator CGI-58 (Comparative Gene Identification-58). Our previous studies have identified G0S2 (G0/G1 Switch Gene 2) as an endogenous inhibitor of ATGL, and have provided compelling evidence that differential expression of G0S2 plays a crucial role in regulating adipose lipolysis, adipose-liver FA flux and hepatic lipid content. Interestingly, we have obtained preliminary evidence that G0S2 also functions independently of ATGL in the glycerol phosphate pathway for TG synthesis. The objective of this application is to further explore the roles of G0S2 in hepatic lipid and energy metabolism, and the development of obesity-associated hepatic steatosis and insulin resistance. The hypothesis of the proposed studies is that by acting downstream of the liver X receptor-? (LXR?), G0S2 is a dual-function protein that possesses activities of both a lipolytic inhibitor and a lysophosphatidic acid acyltransferase (LPAAT). While both functions contribute to hepatic steatosis during fasting and in response to high-fat and high-carbohydrate feeding, G0S2's role as a LPAAT promotes synthesis of phosphatidic acid (PA) and diacylglycerol (DG) in the liver and is responsible for its detrimental effect in mice with diet-induced obesity (DIO). The rationale for the proposed research is that identifying the role of G0S2 in mediating hepatic lipid accumulation will provide significant insight into the etiology of NAFLD and related disorders, thereby advancing the possibilities for development of nutritional or pharmaceutical therapies. The hypothesis will be tested using three specific aims: 1) to characterize the LXR?-G0S2 axis and its role in hepatic lipid metabolism; 2) to determine the physiologic relevance of G0S2 as a LPAAT in promoting hepatic TG accumulation; and 3) to determine the ATGL-independent role of G0S2 in diet-induced insulin resistance. We will perform both gain- and loss-of- function studies by combining the usage of cell biological and physiological approaches established in our laboratory with unique animal models deficient in G0S2, LXR? or ATGL that are available. These studies are innovative because they focus on the roles of a unique dual-function regulator of TG synthesis and hydrolysis in the development of hepatic steatosis and insulin resistance. Understanding how hepatic TG metabolism is regulated is significant because it not only impacts the treatment of NAFLD, but also will advance the field of energy metabolism as it relates to obesity.

Public Health Relevance

The proposed studies will advance our understanding of the mechanisms underlying the development of non- alcoholic fatty liver disease (NAFLD) and its relationship with insulin resistance. The data derived from this project will guide the design of new therapeutic approaches to prevent and treat metabolic diseases associated with obesity, and hence will have a direct effect on human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK109096-04
Application #
9841676
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Teff, Karen L
Project Start
2016-04-01
Project End
2020-07-31
Budget Start
2019-04-01
Budget End
2019-07-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Zhang, Xiaodong; Saarinen, Alicia M; Campbell, Latoya E et al. (2018) Regulation of Lipolytic Response and Energy Balance by Melanocortin 2 Receptor Accessory Protein (MRAP) in Adipocytes. Diabetes 67:222-234
Zhang, Xiaodong; Heckmann, Bradlee L; Campbell, Latoya E et al. (2017) G0S2: A small giant controller of lipolysis and adipose-liver fatty acid flux. Biochim Biophys Acta Mol Cell Biol Lipids 1862:1146-1154
Heckmann, Bradlee L; Zhang, Xiaodong; Saarinen, Alicia M et al. (2017) Liver X receptor?mediates hepatic triglyceride accumulation through upregulation of G0/G1 Switch Gene 2 expression. JCI Insight 2:e88735
Zhang, Xiaodong; Saarinen, Alicia M; Hitosugi, Taro et al. (2017) Inhibition of intracellular lipolysis promotes human cancer cell adaptation to hypoxia. Elife 6:
Heckmann, Bradlee L; Zhang, Xiaodong; Saarinen, Alicia M et al. (2016) Regulation of G0/G1 Switch Gene 2 (G0S2) Protein Ubiquitination and Stability by Triglyceride Accumulation and ATGL Interaction. PLoS One 11:e0156742