Tuesday, November 28, 2023
11/28/2023
PROJECT SUMMARY/ABSTRACT The epidemic of obesity and type 2 diabetes has increased prevalence of associated cardiometabolic diseases including elevated serum triglycerides (TGs) and non-alcoholic fatty liver disease (NAFLD). There is resurgent interest in drugs targeting the hepatic nuclear receptor PPARa. Such fibrate drugs are already used in hypertriglyceridemia, and there is new appreciation that TGs independently cause atherosclerotic cardiovascular disease such that lowering TGs reduces risk. Furthermore, PPAR agonists may be among the first drugs approved for NAFLD. Adverse clinical outcomes in NAFLD like cirrhotic liver failure, hepatocellular carcinoma, and liver-related death are all closely linked to hepatic fibrosis. Our preliminary data in a NAFLD mouse model show unexpectedly that PPARa deficiency and PPARa agonist treatment both fail to change hepatic steatosis, but markedly affect fibrosis (increasing and decreasing it, respectively). PPARa functions in hepatocytes to bind regulatory DNA and affect expression of key genes in lipid metabolism. The related nuclear receptor HNF4a is not a drug target, yet regulates similar genes and binds similar regulatory DNA. We hypothesize that the interplay of PPARa and HNF4a in DNA binding affects hepatocyte gene regulation, relevant to the pathogenesis and therapeutics of NAFLD. Our experiments probe genome-wide nuclear receptor binding sites and gene regulation, in normal and steatotic livers, basally and in response to drugs. Aim 1 defines the interdependency of PPARa and HNF4a in liver gene regulation, using mouse models deficient in either or both. Aim 2 extends these studies of PPARa and HNF4a to NAFLD, in both mouse models and human biospecimens. Aim 3 deploys the powerful tools of genetics to characterize PPARa and HNF4a interplay in sequence-specific DNA binding. By comparing inbred mouse strains, natural polymorphisms affecting binding motifs will reveal mechanisms for selective and common DNA binding by PPARa and HNF4a. In human liver samples, we will test the hypothesis that that non- coding genetic variants in PPARa/HNF4a genomic binding sites underlie some differences among people in TG levels, NAFLD, and response of these to PPARa agonist drugs. Beyond this potential clinical relevance, these studies use innovative genomic and genetic approaches to address key unanswered questions in the biology of PPARa, including its interplay with related nuclear receptors.
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