Life depends upon the conversion of food to energy. However, imbalances in food intake, genetic variations or environmental factors can alter metabolic pathways, causing type 2 diabetes, fatty liver disease, metabolic syndrome or cardiovascular disease. Determining causes and effects in such a complex system is difficult;therefore it is important to identify common regulatory points that may impact multiple metabolic endpoints. Transcription factors from the SREBP (sterol regulatory binding element protein) family coordinate activation of genes necessary for fatty acid, cholesterol and phospholipid biosynthesis (Horton, 2002). They also insure these biosynthetic pathways have adequate building blocks by expressing Acetyl CoA and NADPH synthesis genes. We have found that SREBPs are important for generating another metabolite linked to these processes: s-adenosyl methionine (SAMe). SAMe is produced by the one carbon cycle (1CC) and necessary for phospholipid biosynthesis and epigenetic modification in addition to other cellular processes. A growing body of evidence has linked 1CC function with fatty liver disease and the development of liver cancer (Mato, 2008). Our finding that SREBPs affect expression of key genes in this pathway suggests lipid homeostasis and levels of 1CC metabolites such as methionine, homocysteine, and SAMe may be coordinately regulated. In this proposal, we will combine studies in C. elegans, an invertebrate model with conserved lipid biology, with mechanistic analysis in mammalian cell culture systems to determine which aspects of 1CC are essential for SREBP function in vivo. We will examine if signals directing SREBP activation of fatty acid biosynthesis genes also affect 1CC genes. Phenotypic analysis of a SREBP target in the 1CC has revealed that sams-1 (s-adenosyl methionine syntase) knockdown causes formation of large lipid droplets. These droplets are reminiscent of the hepatic steatosis appearing when the mouse ortholog (MAT1A) is targeted (Mato, 2008) and suggest C. elegans may model aspects of the lipid accumulation in fatty liver disease. C. elegans are amenable to rapid gene inactivation by RNAi, metabolic profiling and dietary manipulation, providing an excellent model for dissecting the regulatory interactions between SREBP and 1CC metabolism which can be expanded in more complex mammalian models. The experiments in this proposal will impact our understating of links between nutrition, metabolism and disease.

Public Health Relevance

Fatty liver disease, type 2 diabetes and cardiovascular disease are characterized by metabolic dysfunction, yet it is difficult to determine how nutritional and genetic factors impact disease progression. The studies in our proposal utilize a simple invertebrate model, C. elegans, to discover links between lipid production and one carbon cycle metabolites such as s-adenosyl methionine and homocysteine and to expand this analysis to mammalian systems. This research will (1) enhance our understanding of how metabolic pathways, critical in human disease, are coordinately regulated and (2) expand our knowledge of the links between nutrition, genetics and disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Haft, Carol R
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University of Massachusetts Medical School Worcester
Other Basic Sciences
Schools of Medicine
United States
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Walker, Amy Karol (2017) 1-Carbon Cycle Metabolites Methylate Their Way to Fatty Liver. Trends Endocrinol Metab 28:63-72
Smulan, Lorissa J; Ding, Wei; Freinkman, Elizaveta et al. (2016) Cholesterol-Independent SREBP-1 Maturation Is Linked to ARF1 Inactivation. Cell Rep 16:9-18
Ding, Wei; Smulan, Lorissa J; Hou, Nicole S et al. (2015) s-Adenosylmethionine Levels Govern Innate Immunity through Distinct Methylation-Dependent Pathways. Cell Metab 22:633-45
Walker, Amy K; Jacobs, René L; Watts, Jennifer L et al. (2011) A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell 147:840-52
Walker, Amy K; Yang, Fajun; Jiang, Karen et al. (2010) Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev 24:1403-17