Hoehn, Kyle Lee, PhD
The paradoxical role of Acetyl-CoA Carboxylase activity in hepatic fatty acid oxidation
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Insulin Action\Transgenic Models, Integrated Physiology, Integrated Physiology\Fatty Acid Metabolism, Integrated Physiology\Liver
Type of Grant: Minority Undergraduate Internship
Project Start Date: January 1, 2013
Project End Date: December 31, 2013
More than 300 million people worldwide suffer from insulin resistance and type 2 diabetes. Liver lipid accumulation is a major risk factor for insulin resistance and type 2 diabetes, so expanding understanding of lipid metabolism mechanisms is essential for developing future treatments. The molecular switch that regulates metabolic flexibility and the shift between glucose and fatty acid oxidation is controlled by acetyl-CoA carboxylase (ACC) enzymes. ACC enzymes produce malonyl-CoA, a negative regulator of fatty acid oxidation. By deleting hepatic ACC activity we expected to observe that fatty acid oxidation would be increased and would result in a lean liver.
However, we demonstrate the opposite result wherein mice lacking hepatic ACC activity have reduced fatty acid oxidation and more triglyeride storage. My project for this internship is to determine the role of protein acetylation in this paradoxical phenotype. We hypothesize that loss of ACC activity causes the accumulation of its substrate acetyl-CoA and increases the availability of acetyl-CoA to acetyltransferases. We observe that ACC mutant mice have global hyperacetylation therefore we will specifically test whether blocking protein acetylation can reverse the fatty acid oxidation phenotype.
Mentor: Kyle Lee Hoehn
Undergraduate: Jason Liao
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
More than 300 million people worldwide are insulin resistant or have type 2 diabetes. Obesity, hepatic steatosis, and non-alcoholic fatty liver disease are causally linked to these disorders. Our lab has established multiple approaches to block the liver's ability to produce fat from biosynthetic precursors such as glucose. The prediction is that the liver should not produce excess fat and will be leaner and more insulin sensitive. However, we've discovered a compensatory mechanism whereby the liver senses low levels of new lipid production and increases scavenging of fats from the circulation resulting in a fatty liver. We are currently exploring the mechanism whereby this counter-regulation occurs. This project will advance our understanding of the molecular regulation of fat balance in the liver and will be important for the development of new anti-diabetes therapeutics.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
This project will improve our understanding of how the liver can be manipulated to alter fat storage, glucose metabolism, and insulin sensitivity. The overall goal is to identify new ways to reduce hepatic fat and improve insulin sensitivity. This would result in better glycemic control and would ultimately help diabetics control blood sugar levels.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
Unfortunately I have family members with type 2 Diabetes. The personal motivation to study diabetes derives from my first hand observation of the debilitating consequences of this disease. I started my career twelve years ago in a diabetes research laboratory and I will continue to spend the rest of my career helping to find a cure for this disease. Support from the ADA has been absolutely crucial for my research efforts over the past three years and has enabled my laboratory to make considerable progress. The support of the minority undergraduate internship has allowed me to hire and train a future diabetes scientist.
In what direction do you see the future of diabetes research going?
This is an exciting time in diabetes research. In the last decade we've seen many new drugs come to the market and we've learned a lot from the multitude of clinical trials that have been conducted. The future of diabetes therapy is set to change from primarily being a 'diabetes management' strategy to a 'diabetes reversal' strategy. Research has been critical for this transition and research will continue to be essential until we identify a cure.
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