Role of acetyl-CoA metabolism in the response to dietary and thermal stress

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PROJECT SUMMARY Metabolic diseases including non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, and cardiovascular disease, which are linked to obesity, pose a major threat to economic and healthcare systems worldwide. Accordingly, there is a great need for new therapeutic targets and strategies. Abnormal lipid metabolism, especially in the liver, is a hallmark of metabolic disease, and the enzyme ATP-citrate lyase (ACLY), which generates acetyl-CoA for lipid and cholesterol synthesis, has emerged as a promising therapeutic target against fatty liver. To this point, several ACLY inhibitors are in development for clinical use, and one that specifically targets hepatic ACLY has been FDA approved against high cholesterol. However, it is now appreciated that there are multiple routes to lipogenic acetyl-CoA that are tissue and diet dependent. For example, lipogenic acetyl-CoA can also be derived from acetate via acetyl-CoA synthetase 2 (ACSS2) in certain dietary contexts, and emerging data indicates additional pathways to lipogenic acetyl-CoA likely exist. Moreover, work in the last decade has conclusively shown that lipid homeostasis in humans requires coordination between the body’s thermal regulatory organs (brown adipose tissue) and its energy storing and distribution centers (the liver and white adipose tissue), which is corroborated by studies in murine models further indicating that brown fat and liver and the two most lipogenic organs. The implications of these discoveries are that targeting ACLY systemically in one tissue or dietary context may be beneficial while targeting it in another may be detrimental. Indeed, our published and preliminary data supported by this grant show there is considerable interplay between the ACLY and ACSS2 pathways in brown and white adipose tissues and liver that is both context (i.e. diet and temperature) dependent and compensatory. Thus, effectively deploying ACLY or ACSS2 inhibitors will require a much deeper understanding of the tissue, diet, and thermoregulatory dependent mechanisms by which lipogenic acetyl-CoA is synthesized and utilized in vivo. In this proposal, we leverage tools and techniques generated in the previous funding period to investigate the biological functions of ACLY and ACSS2 in thermogenic adipocytes (Aim 1) and hepatocytes (Aim 2). Our approach utilizes tissue-specific single and double knockout models of ACLY and ACSS2 that we have generated, and techniques in metabolomics, compartmentalized metabolite analysis, and in vivo stable isotope tracing that we have adapted for studying adipose tissues and liver. This work will be facilitated by a team of researchers with complementary expertise and who have collaborated productively for several years. Our long- term goal is to identify optimal strategies, such as drug/diet combination therapies, to help patients suffering from metabolic diseases.