The metabolic syndrome is a state of insulin resistance characterized by multiple derangements in lipid homeostasis, leading to dyslipidemia, atherosclerosis, hepatic steatosis, and cholesterol gallstones. The factors that drive these derangements are unknown but must be determined in order to effectively treat the metabolic syndrome. The transcription factors FoxO1 and Sterol Regulatory Element Binding Protein (SREBP)-1c are key regulators of insulin action. FoxO1 promotes transcription of the gluconeogenic enzymes, but also the enzymes necessary for VLDL secretion and biliary cholesterol secretion. SREBP-1c, on the other hand, induces the lipogenic enzymes. In normal livers, insulin suppresses FoxO1 and activates SREBP-1c. In the metabolic syndrome, insulin fails to suppress FoxO1 but SREBP-1c is paradoxically increased. This raises the question, what drives SREBP-1c in the presence of insulin resistance? Our preliminary data show that the livers of Liver Insulin Receptor Knockout (LIRKO) mice, which are unresponsive to insulin, show a rapamycin- sensitive increase in SREBP-1c in response to dietary carbohydrates. These data indicate the existence of an insulin-independent signaling pathway that could potentially allow the excessive consumption of carbohydrates to activate SREBP-1c and lipogenesis, even in the presence of insulin resistance. The overarching goal of this proposal is to identify the key driver of lipid metabolism in the insulin resistant state. We hypothesize that FoxO1, which fails to be suppressed by insulin, drives dyslipidemia, atherosclerosis and gallstones;but that SREBP-1c, induced by nutrients, drives lipogenesis and steatosis.
Our aims are to (1) determine the extent to which FoxO1 and SREBP-1c promote atherosclerosis, steatosis, and cholesterol gallstones by knocking down FoxO1 or reconstituting SREBP-1c expression in the livers of LIRKO mice;and (2) to define the insulin-independent signaling pathways by which nutrients can activate SREBP-1c and lipogenesis. We expect to find that FoxO1 and SREBP-1c define two distinct metabolic signaling pathways that are both necessary for the full complement of derangements present in the metabolic syndrome.

Public Health Relevance

The metabolic syndrome affects approximately one third of adults in the United States. Much of the morbidity and mortality associated with this disorder can be ascribed to derangements in lipid homeostasis: dyslipidemia, atherosclerosis, cholesterol gallstones, and hepatic steatosis. The studies here will identify the key regulatory molecules that drive these derangements, and ultimately lead to more rational and effective therapies for the metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK094162-01A1
Application #
8297577
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Laughlin, Maren R
Project Start
2012-05-19
Project End
2016-04-30
Budget Start
2012-05-19
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$378,450
Indirect Cost
$160,950
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Hu, Yue; Semova, Ivana; Sun, Xiaowei et al. (2018) Fructose and glucose can regulate mammalian target of rapamycin complex 1 and lipogenic gene expression via distinct pathways. J Biol Chem 293:2006-2014
Meoli, Luca; Gupta, Nitin K; Saeidi, Nima et al. (2018) Nonalcoholic fatty liver disease and gastric bypass surgery regulate serum and hepatic levels of pyruvate kinase isoenzyme M2. Am J Physiol Endocrinol Metab 315:E613-E621
Ling, Alisha V; Gearing, Mary E; Semova, Ivana et al. (2018) FoxO1 Is Required for Most of the Metabolic and Hormonal Perturbations Produced by Hepatic Insulin Receptor Deletion in Male Mice. Endocrinology 159:1253-1263
Levenson, A E; Milliren, C E; Biddinger, S B et al. (2017) Calorically restricted diets decrease PCSK9 in overweight adolescents. Nutr Metab Cardiovasc Dis 27:342-349
Hu, Yue; Shin, Dong-Ju; Pan, Hui et al. (2017) YAP suppresses gluconeogenic gene expression through PGC1?. Hepatology 66:2029-2041
Key, Chia-Chi C; Liu, Mingxia; Kurtz, C Lisa et al. (2017) Hepatocyte ABCA1 Deletion Impairs Liver Insulin Signaling and Lipogenesis. Cell Rep 19:2116-2129
Sun, Xiaowei; Haas, Mary E; Miao, Ji et al. (2016) Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation. J Biol Chem 291:1115-22
Kassai, Andrea; Muniyappa, Ranganath; Levenson, Amy E et al. (2016) Effect of Leptin Administration on Circulating Apolipoprotein CIII levels in Patients With Lipodystrophy. J Clin Endocrinol Metab 101:1790-7
Kim, Don-Kyu; Kim, Yong-Hoon; Hynx, Debby et al. (2014) PKB/Akt phosphorylation of ERR? contributes to insulin-mediated inhibition of hepatic gluconeogenesis. Diabetologia 57:2576-85
Kurtz, C Lisa; Peck, Bailey C E; Fannin, Emily E et al. (2014) MicroRNA-29 fine-tunes the expression of key FOXA2-activated lipid metabolism genes and is dysregulated in animal models of insulin resistance and diabetes. Diabetes 63:3141-8

Showing the most recent 10 out of 12 publications