Obesity is associated with continuous exposure of liver to high levels of fats, which over time induces abnormal fat accumulation in liver cells and leads to fatty liver and tissue malfunction. Eventually, these changes can result in insulin resistance and type 2 diabetes. The molecular causes that initiate this cycle of negative events remain unclear. I have discovered a novel molecular pathway that serves to adjust liver fat breakdown to fat supply, which maintains energy balance and normal function. I am proposing to examine if disruption of this pathway results in abnormal fat handling that is detrimental to liver health.
I have discovered that high fat regulates the function of AMPK and PI3K, intracellular proteins that are master coordinators of liver energy utilization. High fat alters the association between proteins important for proper function of AMPK and PI3K. The specific questions I will ask are:
1. How does high fat regulate AMPK and PI3K?
2. Does obesity alter communication between the proteins involved in AMPK and PI3K function?
3. Does obesity cause disruption of cellular energy metabolism and insulin resistance?
I will use liver cells and mice with altered liver levels of proteins that are important for the regulation of AMPK and PI3K function. I anticipate my study will provide novel insights into the molecular mechanisms that link obesity to the development of abnormal liver function. The findings should allow the design of therapeutic approaches that can target the link between CD36 and AMPK to enhance fat breakdown by the liver and decrease liver fat accumulation.
Obesity is a major cause of insulin resistance and type 2 diabetes (T2D), conditions that continue to increase in prevalence worldwide. Insulin resistance is at the core of metabolic syndrome (MetS), which involves more than 25% of the population with an even higher incidence in some subpopulations such as African Americans. CD36, the fatty acid (FA) receptor studied in this project, has been linked to a metabolic disease.
Our recent findings indicate that hepatocyte CD36 is involved in the regulation of the IR (insulin receptor) in the liver and this modulates insulin action on glucose and lipid metabolism, including de-novo lipogenesis (DNL) and hepatic glucose production (HGP). We also identify the influence of hepatic CD36 in transcriptional effects of insulin on Pcsk9 (Proprotein convertase subtilisin/kexin type 9) and Angptl3 (Angiopoietin-like 3), which are essential effectors of triglyceride (TG)/lipoprotein clearance. These findings suggest a link between CD36 signaling, FA flux and insulin action in regulation of liver metabolism and function in lipoprotein clearance. This is highly relevant to our understanding of hepatic insulin sensitivity and diabetic dyslipidemia and etiology of cardiovascular disease.
We anticipate that this study will provide novel insights into the molecular mechanisms that link obesity to the development of fatty liver, abnormal blood lipids, and heart disease. The findings would validate the use of novel diagnostic markers that would predict the risk for the development of fatty liver and heart disease.