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Grants and Contracts Details
Description
There is little doubt that we are in the midst of a worldwide epidemic of obesity. Almost two-thirds of adults in the
United States are obese or overweight. Whether if obesity arises from genetic factors or high caloric intake, it
still may lead to insulin resistance and type II diabetes. Our recent data show that bilirubin (BR), which has been
typically considered as an antioxidant, may function as a metabolic ligand that signals to the nuclear receptor
transcription factor PPARα to reduce lipid accumulation. We also found that BR induces the hepatic fibroblast
growth factor 21 (FGF21) hormone via PPARα, which is known to have systemic effects on insulin sensitivity.
Hepatic lipid accumulation and insulin resistance are interlocking pathophysiologic events, but the mechanisms
of these abnormalities, and how these distinct processes interact, are inadequately understood. For unknown
reasons, BR plasma levels are lower in the obese, and several obese patients progress to nonalcoholic fatty
liver disease (NAFLD), which is likely due to obesity-induced insulin resistance. However, in patients with
pathological liver disease such as Crigler-Najjar syndrome, the BR plasma levels are very high. This paradox
may be explained by the hepatic UDP-glucuronosyltransferase 1-1 (UGT1A1) enzyme that conjugates BR to
make it soluble and for deposition into bile and eventually into the intestine, which lowers unconjugated BR from
the blood. In humans, a polymorphism in the UGT1A1 gene (UGT1A1*28), known as Gilbert’s syndrome (GS),
reduces expression resulting in increased plasma BR levels but not in liver disease. We have shown that
humanized mice with the Gilbert’s polymorphism (UGT1A1*28) on a high-fat diet have significantly higher plasma
BR levels, reduced adiposity and insulin intolerance, and are resistant to fatty liver disease. Agents that regulate
Ugt1a1 during weight gain or loss are unknown. In the preliminary data, we show exciting data that microRNA-
365 (miR365) suppresses Ugt1a1 expression and increases plasma BR levels. We also found that Ugt1a1
expression is higher in the livers of obese mice, while miR365 and plasma BR levels are lower, which indicates
that miR365 targeting Ugt1a1 may be beneficial in increasing plasma BR to regulate adiposity. Our central
hypothesis is that BR functions as a metabolic ligand that activates the liver PPARα-FGF21 pathway to reduce
adiposity and insulin resistance. We will pursue this plan with three primary scientific aims: 1) Determine the
selectivity of BR on PPAR isoforms; 2) Determine the systemic effects of BR mediated by hepatic FGF21; and,
3) Determine if miR365 elevation of BR reduces adiposity and insulin resistance via PPARα. Collectively, this
project is the first systematic investigation of the BR-PPARα-FGF21 module and its control of insulin resistance
associated with obesity. The proposal provides advances to new strategies (miR365) of targeting this module to
control adiposity which offers therapeutic benefits.
Status | Active |
---|---|
Effective start/end date | 7/3/20 → 3/31/26 |
Funding
- National Institute Diabetes & Digestive & Kidney: $2,177,141.00
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Projects
- 1 Active
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Diversity Supplement for Genesee Martinez: Novel Liver Signaling Pathways Controlling Adiposity
Hinds, T. (PI) & Swanson, H. (CoI)
National Institute Diabetes & Digestive & Kidney
7/3/20 → 3/31/25
Project: Research project