Long noncoding RNA regulation of hepatic lipogenesis and NAFLD

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

? DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological condition that is increasingly recognized as a component of the epidemic of obesity. It can cause a spectrum of liver damage, ranging from simple fatty liver with uncomplicated steatosis to progressive nonalcoholic steatohepatitis (NASH) which increases the risk of ?brosis and cirrhosis. The deposition of excess triglycerides within liver cells is a hallmark of NAFLD and NASH. In previous studies, several transcriptional factors and microRNAs have been identifyed that regulate hepatic lipogenesis and lipid accumulation. However, whether long noncoding RNAs (lncRNAs), an emerging class of developmental regulators, participate in the modulation of hepatic lipid metabolism has not been explored. Dr. Zhao recently identified brown fat lncRNA 1 (Blnc1) as a novel lncRNA regulator of brown/beige adipocyte differentiation and function. Blnc1 promotes brown/beige adipocyte differentiation and function by forming a feedforward regulatory loop with early B-cell factor 2 (EBF2) to drive adipogenesis toward thermogenic phenotype. In preliminary studies, Dr. Zhao found that liver Blnc1 expression was induced in response to the fasting/refeeding switch and significantly elevated in diet-induced and genetically obese mice. Adenoviral-mediated overexpression of Blnc1 in mice increased liver triglyceride content accompanied by augmented expression of Sterol regulatory element binding protein 1c (SREBP1c) and its downstream genes involved in de novo lipogenesis. At the molecular level, Blnc1 acted cooperatively with Liver X receptor (LXR) to induce SREBP1c in a cell-autonomous manner. Based on these exciting findings, Dr. Zhao's research strategy is designed to address the hypothesis that Blnc1 regulates SREBP1c and facilities the activation of hepatic lipogenesis through its formation of ribonucleoprotein transcriptional complexes with LXR. In this proposal, Dr. Zhao plan to define the role of Blnc1 in hepatic lipid metabolism and elucidate mechanistic framework for the LXR/Blnc1 pathway (K99 Mentored Phase). Finally, Dr. Zhao will generate liver-specific Blnc1 deficient mice to evaluate the role of Blnc1 in the activation of hepatic lipogenesis and the significance of this pathway in NAFLD linked to obesity (R00 Independent Phase). Successful completion of this project will therefore provide fundamental insights into an important area of metabolic research and advance our understanding of pathogenic mechanisms of obesity and its associated disorders.