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.

Public Health Relevance

Non-alcoholic fatty liver disease (NAFLD) is emerging as a major risk factor for end-stage liver disease and there is an urgent unmet medical need for therapeutic intervention. The proposed work will elucidate a novel mechanism that potentially drives the activation of hepatic lipogenesis during obesity and exacerbates hepatic steatosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Career Transition Award (K99)
Project #
1K99DK106664-01A1
Application #
9107557
Study Section
Digestive Diseases and Nutrition C Subcommittee (DDK-C)
Program Officer
Saslowsky, David E
Project Start
2016-07-01
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$90,000
Indirect Cost
$6,667
Name
University of Michigan Ann Arbor
Department
Type
Organized Research Units
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhao, Xu-Yun; Xiong, Xuelian; Liu, Tongyu et al. (2018) Long noncoding RNA licensing of obesity-linked hepatic lipogenesis and NAFLD pathogenesis. Nat Commun 9:2986
Zhao, Xu-Yun; Li, Siming; DelProposto, Jennifer L et al. (2018) The long noncoding RNA Blnc1 orchestrates homeostatic adipose tissue remodeling to preserve metabolic health. Mol Metab 14:60-70
Li, Siming; Mi, Lin; Yu, Lei et al. (2017) Zbtb7b engages the long noncoding RNA Blnc1 to drive brown and beige fat development and thermogenesis. Proc Natl Acad Sci U S A 114:E7111-E7120
Chen, Zhimin; Wang, Guo-Xiao; Ma, Sara L et al. (2017) Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders. Mol Metab 6:863-872
Mi, Lin; Zhao, Xu-Yun; Li, Siming et al. (2017) Conserved function of the long noncoding RNA Blnc1 in brown adipocyte differentiation. Mol Metab 6:101-110