R16GM150498

Investigating the role of lipocalin prostaglandin D2 synthase and its metabolite PGD2 in non-alcoholic fatty liver disease - Project summary/abstract

Despite non-alcoholic fatty liver disease (NAFLD) being the most common chronic liver disease worldwide, molecular mechanisms contributing to its etiology and progression are still unclear.

This gap in knowledge has prevented the understanding of basic biology, pathogenesis, and the development of novel therapeutics for NAFLD.

There is currently no FDA-approved therapy for NAFLD.

A vast majority of prior studies that investigated NAFLD were performed primarily on obese models since obesity and NAFLD are strongly intertwined.

Despite these studies, the role of insulin resistance in NAFLD is unclear.

Interestingly, our preliminary data demonstrated that L-PGDS knockout mice exhibited a NAFLD phenotype along with significant insulin resistance and weight gain on high-fat diet.

Lipocalin prostaglandin D2 synthase (L-PGDS) functions as a prostaglandin synthase where it catalyzes the isomerization of PGH2 to PGD2.

PGD2 regulates its physiological function through two individual G-protein coupled receptors named DP1 and DP2.

Therefore, we hypothesized that the lack of PGD2 will induce fatty liver disease possibly involving hepatic insulin resistance and obesity.

The objective of this SURE first application is to investigate the role of L-PGDS and its metabolite PGD2 in NAFLD.

Aim 1 of the current proposal is dedicated on elucidating the effect of insulin signaling on L-PGDS mRNA and protein expression, localization, and function.

Next, we will be investigating the role of L-PGDS on glucose and lipid metabolism through studying energy substrate utilization, glycolysis, and fatty acid oxidation.

Additionally, metabolomics and transcriptomics unbiased approaches will discover L-PGDS-regulated signaling pathways in NAFLD.

Aim 3 is dedicated to determining the role of PGD2 receptor modulators, DP1 and DP2 receptor agonist and antagonist, in NAFLD using insulin-resistant HepG2 cells and db/db mice subjected to high fat diet.

The significance of the proposed research is that, once hepatic regulation of L-PGDS signaling is understood, targets for NAFLD pharmacotherapy could be developed.

This work is innovative as it elucidates the novel role of L-PGDS in fatty liver disease and defines its link to insulin resistance and obesity that is supported by our preliminary data.

Collectively, our research will shed new light on the role of L-PGDS in liver physiology and diabetes- and obesity-induced NAFLD and discover new therapeutic targets for future studies.

St. John's University, New York

THE NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES (NIGMS) SUPPORTS BASIC RESEARCH THAT INCREASES OUR UNDERSTANDING OF BIOLOGICAL PROCESSES AND LAYS THE FOUNDATION FOR ADVANCES IN DISEASE DIAGNOSIS, TREATMENT, AND PREVENTION. NIGMS ALSO SUPPORTS RESEARCH IN SPECIFIC CLINICAL AREAS THAT AFFECT MULTIPLE ORGAN SYSTEMS: ANESTHESIOLOGY AND PERI-OPERATIVE PAIN, CLINICAL PHARMACOLOGY ?COMMON TO MULTIPLE DRUGS AND TREATMENTS, AND INJURY, CRITICAL ILLNESS, SEPSIS, AND WOUND HEALING.? NIGMS-FUNDED SCIENTISTS INVESTIGATE HOW LIVING SYSTEMS WORK AT A RANGE OF LEVELSFROM MOLECULES AND CELLS TO TISSUES AND ORGANSIN RESEARCH ORGANISMS, HUMANS, AND POPULATIONS. ADDITIONALLY, TO ENSURE THE VITALITY AND CONTINUED PRODUCTIVITY OF THE RESEARCH ENTERPRISE, NIGMS PROVIDES LEADERSHIP IN SUPPORTING THE TRAINING OF THE NEXT GENERATION OF SCIENTISTS, ENHANCING THE DIVERSITY OF THE SCIENTIFIC WORKFORCE, AND DEVELOPING RESEARCH CAPACITY THROUGHOUT THE COUNTRY.

93.859 - Biomedical Research and Research Training

National Institute of General Medical Sciences (NIGMS) [HHS - NIH]

Jamaica, New York 114399000 United States

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Support for Research Excellence First Independent Research (SuRE-First) Award (R16 - Clinical Trial Not Allowed) (PAR-21-173)

Amendment Since initial award the total obligations have increased 100% from $187,500 to $375,000.