University of Illinois at Chicago
SHEN-DISSERTATION-2016.pdf (6.44 MB)

Mechanistic Investigations of Lipotoxicity in Non-Alcoholic Fatty Liver Disease

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posted on 2017-02-17, 00:00 authored by Chen Shen
Lipotoxicity is regard as the central mechanism underlying Non-Alcoholic Fatty Liver Disease (NAFLD), however, the exact mechanism of lipotoxicity remains to be understood. Saturated fatty acids (SFAs) induces hepatic cell death, and is used as an in vitro model for the study of lipotoxicity. In this thesis, the molecular mechanisms underlying SFA-induced lipotoxicity are being studied. In the liver, lipotoxicity induces ER stress. In the first study, we first examined the pattern of PA-induced cell death in hepatocytes, and confirmed the induction of ER stress upon PA exposure. Interestingly, we showed an involvement of TLR4, evidenced by up-regulated gene expression and signaling activation. Furthermore, inhibition of TLR4 prevents the activation of IRE1α branch of ER stress. Collectively, our data uncovers the existence of a possible link between TLR4 and ER stress, which contributes to PA-induced lipotoxicity. The second study showed a protective function of Nicotinamide (NAM), a form of Vitamin B3, in PA-induced lipotoxicity. Further mechanistic investigation indicated that NAM supplementation led to the induction of autophagy, a cellular event for degradation and recycling, evidenced by LC3-II formation and p62 consumption, which conferred the anti-lipotoxic effect of NAM in hepatocytes. Notably, the up-regulations of SIRT1, a human sirtuin, is observed upon NAM exposure, which contributes to both the autophagy inducing and the cytoprotective effect of NAM. These results altogether indicated the therapeutic potential of NAM in lipotoxicity. Lastly, we studied the role of SIRT3, a human mitochondria sirtuin, in PA-induced lipotoxicity. In hepatocytes exposed to PA, we observed an increased SIRT3 abundance and activity, evidenced by hypo-acetylation of mitochondrial proteins. Unexpectedly, SIRT3 knockdown in hepatocytes exhibited protection against PA-induced lipotoxicity. Further mechanistic investigations showed that SIRT3 knockdown resulted in the activation of AMPK, which contributed to the protective function of SIRT3 gene silencing. Hepatocytes co-transfected with both SIRT3 siRNA and AMPK siRNA abolished to protection conferred by SIRT3 knockdown alone.



Song, Zhenyuan


Song, Zhenyuan


Kinesiology and Nutrition

Degree Grantor

University of Illinois at Chicago

Degree Level

  • Doctoral

Committee Member

Fantuzzi, Giamila Koh, Timothy Varady, Kristina Diamond, Alan

Submitted date

December 2016

Issue date


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