Non alcoholic fatty liver disease (NAFLD) is estimated to affect up to one third of the general population and there is a strong relationship between NAFLD, hepatic insulin resistance and type 2 diabetes (T2D). NAFLD is also a key predisposing factor for the development of non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma and it is anticipated that NAFLD-induced NASH will soon surpass hepatitis C and alcoholic cirrhosis as the most common indication for liver transplantation in the USA. Therefore there is a great unmet need for new drugs that are effective at reducing hepatic steatosis and hepatic insulin resistance. In this grant we will examine the chronic effects of a novel liver-targeted small molecule inhibitor of acetyl-CoA carboxylase on hepatic triglyceride content as well as hepatic glucose and lipid metabolism in NAFLD subjects in a randomized double-blinded placebo-controlled parallel group study. Specifically we will examine the chronic (21 days) effects of a novel liver-targeted small molecule inhibitor of acetyl-CoA carboxylase on: 1) Hepatic triglyceride content assessed by 1H magnetic resonance spectroscopy (MRS), 2) Hepatic, skeletal muscle and adipocyte insulin sensitivity assessed by a hyperinsulinemic-euglycemic clamp in conjunction with [6,6-2H2]glucose, [2H5]glycerol, and [13C16]palmitate turnover, 3) Rates of hepatic mitochondrial oxidation directly assessed by in vivo 13C magnetic resonance spectroscopy, 4) Rates of hepatic ketogenesis assessed by [13C4]?-hydroxybutyrate turnover, 5) Hepatic de novo lipogenesis (DNL) and gluconeogenesis assessed by 2H2O, 6) Relative flux rates of hepatic pyruvate carboxylase flux (VPC)/citrate synthase flux (VCS) assessed by a novel Positional Isotopomer NMR Tracer Analysis (PINTA) method and 7) Whole body energy expenditure, VO2, VCO2, respiratory quotient assessed by indirect calorimetry. We hypothesize that chronic inhibition of acetyl-CoA carboxylase will result in decreased hepatic steatosis due to increased hepatic mitochondrial fat oxidation and decreased DNL. We also anticipate that this reduction in hepatic steatosis will be associated with improved hepatic insulin sensitivity as reflected by increased suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. The results of these studies will provide important new proof of concept data in support of liver-targeted acetyl CoA carboxylase inhibition as a therapy for NAFLD and T2D as well as fundamental new insights into the mechanisms by which liver-targeted acetyl CoA carboxylase inhibition reduces hepatic steatosis, decreases hepatic insulin resistance and alters hepatic mitochondrial fat oxidation. !

Public Health Relevance

Type 2 diabetes (T2D) and non alcoholic fatty liver disease (NAFLD) are emerging as two of the most critical global health challenges of the 21st century and there is a great unmet need for new therapies. This grant will provide proof of concept data and mechanistic insights in support of a novel drug therapy for NAFLD and T2D. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK113984-01
Application #
9361162
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Teff, Karen L
Project Start
2017-09-15
Project End
2022-07-31
Budget Start
2017-09-15
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Goedeke, Leigh; Bates, Jamie; Vatner, Daniel F et al. (2018) Acetyl-CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents. Hepatology 68:2197-2211
Gassaway, Brandon M; Petersen, Max C; Surovtseva, Yulia V et al. (2018) PKC? contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling. Proc Natl Acad Sci U S A 115:E8996-E9005
Perry, Rachel J; Peng, Liang; Cline, Gary W et al. (2018) Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes. Cell Metab 27:210-217.e3
Samuel, Varman T; Shulman, Gerald I (2018) Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell Metab 27:22-41
Abulizi, Abudukadier; Camporez, João-Paulo; Zhang, Dongyan et al. (2018) Ectopic lipid deposition mediates insulin resistance in adipose specific 11?-Hydroxysteroid dehydrogenase type 1 transgenic mice. Metabolism :
Perry, Rachel J; Wang, Yongliang; Cline, Gary W et al. (2018) Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation. Cell 172:234-248.e17
Petersen, Max C; Shulman, Gerald I (2018) Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev 98:2133-2223
Wang, Yongliang; Nasiri, Ali R; Damsky, William E et al. (2018) Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer. Cell Rep 24:47-55
Madiraju, Anila K; Qiu, Yang; Perry, Rachel J et al. (2018) Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med 24:1384-1394
Goldberg, Ira J; Reue, Karen; Abumrad, Nada A et al. (2018) Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 138:305-315

Showing the most recent 10 out of 13 publications