Overnutrition and physical inactivity promote the accumulation of sphingolipids such as ceramides which block insulin signaling and anabolic metabolism. Implementation of pharmacological or genetic interventions to block ceramide synthesis in rodents prevents or reverses an impressive array of metabolic pathologies (e.g. insulin resistance, diabetes, steatohepatitis, hypertension, cardiomyopathy, and atherosclerosis). Herein we aim to evaluate the therapeutic potential of inhibiting dihydroceramide desaturase-1 (DES1), our preferred target in the ceramide synthesis pathway, in the treatment of insulin resistance and non-alcoholic fatty liver disease.
Aims will involve the following: 1. Evaluating the consequences of inhibiting DES1 on metabolic disorders in mice 2. Determining the mechanism by which the subtle molecular changes to ceramides caused by DES1 inhibition alter cellular function Findings obtained from these studies could lead to new pharmacological approaches for treating diabetes and other cardiometabolic diseases.

Public Health Relevance

Ceramides are fat metabolites that accumulate in individuals susceptible to diabetes and heart disease. Blocking their production in rodents improves both conditions. Herein we aim to investigate the potential of therapeutics that inhibit dihydroceramide desaturase-1, an enzyme required for ceramide biosynthesis, in the treatment of diabetes and heart disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK122001-02
Application #
9977193
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Li, Yan
Project Start
2019-07-15
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Utah
Department
Nutrition
Type
Sch Allied Health Professions
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112