Obesity is associated with an increased risk of a number of chronic and progressive diseases and obesity- related metabolic diseases constitute a significant public health burden. The increased likelihood of developing insulin resistance and diabetes is probably the most commonly recognized risk of being obese. In addition, obesity is also associated with accumulation of lipid in the liver parenchyma (hepatic steatosis or nonalcoholic fatty liver disease (NAFLD)). The term, NAFLD, encompasses both hepatic steatosis (the accumulation of neutral lipid within the cytosol of hepatocytes) and the more severe nonalcoholic steatohepatitis (NASH) (hepatic inflammation and fibrosis associated with steatotic lesions). A significant proportion of NAFLD and NASH patients will progress to cirrhosis and liver failure and are at increased risk for developing hepatocellular carcinoma. NASH is currently a disease without an approved treatment and constitutes a significant unmet medical need. Importantly, inflammation, insulin resistance, and diabetes are tightly linked to development of NASH and thus drugs that target these contributing pathways are lead candidates for treating the disease. This application is designed to test the efficacy of new insulin-sensitizing agents that act via a novel mechanism to improve insulin action while reducing side effects. We will study a novel prototype compound (MSDC-5514) and its backup (MSDC-5445) for efficacy at treating insulin resistance and NASH. In Phase I, we will determine whether these compounds improve insulin sensitivity and test the hypothesis that phospholipase D 1 (PLD1) signaling is their molecular target. In Phase II, we will examine the hepatic effects of MSDC-5514 and MSDC-5445 in a mouse model of NASH and validate PLD1 genetically in this model. Findings obtained in these studies will define mechanisms and provide proof-of- concept evidence supporting future clinical trials to test the efficacy of these drugs in patients with diabetes and other obesity-related cardiometabolic diseases that have the potential to benefit millions of Americans.
Public Health Relevance Statement: Obesity is associated with increased risk of developing metabolic diseases including type 2 diabetes and fatty liver disease. This project is designed to test the effects of new compounds as therapeutics for treating these metabolic diseases in mice. If successful, these studies could pave the way to clinical trials to determine whether these drugs are effective in people as well.
Project Terms: American; Antidiabetic Drugs; B-Lymphocytes; base; Bioavailable; Biochemical; Biological Assay; Blood Glucose; Blood Preservation; cardiometabolism; Chronic Disease; Cirrhosis; Clinical Trials; Collaborations; Comorbidity; CRISPR interference; Cytosol; Data; design; Development; Diabetes Mellitus; Diet; Disease; drug efficacy; Drug Targeting; Drug usage; efficacy testing; Excretory function; Fatty acid glycerol esters; Fatty Liver; Fibrosis; Future; Glucose; Glucose Clamp; glucose production; Hepatic; Hepatocyte; Homeostasis; improved; In Vitro; in vivo; Inflammation; inhibitor/antagonist; Insulin; Insulin Resistance; insulin secretion; insulin sensitivity; insulin sensitizing drugs; intrahepatic; lead candidate; Lesion; Link; Lipids; Liver diseases; Liver Failure; liver injury; Liver parenchyma; Mediating; Medical; Metabolic; Metabolic Diseases; Metformin; Modeling; Molecular; Molecular Analysis; Molecular Target; mouse model; Mus; non-alcoholic fatty liver disease; Non-Insulin-Dependent Diabetes Mellitus; nonalcoholic steatohepatitis; novel; Obese Mice; Obesity; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase; Phenotype; Phospholipase D; phospholipase D1; Phospholipases A; Primary carcinoma of the liver cells; Progressive Disease; prototype; Public Health; Refractory; Risk; Rodent; screening; side effect; Signal Transduction; stellate cell; Sulfonylurea Compounds; Testing; Therapeutic; Therapeutic Effect; Thiazolidinediones; Tissues; Toxicology; urinary; Validation; Work
