junjieliver.png

Notch as a Causal Factor for NAFLD/NASH and Dyslipidemia

My lab has discovered the novel role of Notch, and regulators of Notch signaling, to mediate hepatic lipid metabolism. This research direction arose from the unexpected discovery that hepatocyte-specific Notch loss-of-function, or pharmacologic administration of a range of Notch inhibitors, led to a reduction in hepatic steatosis due to reduced de novo lipogenesis (Pajvani et al, Nature Medicine, 2013). To validate this, we conducted cross-sectional studies in patients undergoing liver biopsy, revealing positive correlations between hepatic Notch activity and markers of insulin resistance and hepatic triglyceride content, but independent and strongest associations with biochemical and pathologic markers of NASH (Valenti et al, Diabetes, 2013). Returning to the bench, using parallel genetic and pharmacologic approaches, we found that inhibition of hepatocyte Notch activity abrogates obesity-induced steatohepatitis and liver fibrosis, while mice with hepatocyte-specific Notch gain-of-function show exacerbated phenotypes due to increased hepatocyte secretion of the fibrogenic factor, Osteopontin (Zhu et al, Science Translational Medicine, 2018). This study also developed a novel Notch inhibitor (Nicastrin ASO) – in parallel work, we found that Nicastrin ASO reduced diet-induced dyslipidemia, due to blockade of γ-secretase complex inactivating cleavage of the LDL Receptor, leading to increased liver VLDL/LDL particle uptake (Kim et al, Cell Metabolism, 2018).

  1. Pajvani UB, Qiang L, Kangsamaksin T, Kitajewski J, Ginsberg HN, Accili D. Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. Nature Medicine, 2013. DOI: 10.1038/nm.3259 | PubMed

  2. Valenti L, Mendoza RM, Rametta R, Maggioni M, Kitajewski C, Shawber CJ and Pajvani UB. Hepatic Notch signaling correlates with insulin resistance and non-alcoholic fatty liver disease. Diabetes, 2013. DOI: 10.2337/db13-0769 | PubMed

  3. Kim K, Goldberg IJ, Graham MJ, Sundaram M, Bertaggia E, Lee S, Qiang L, Haeusler RA, Metzger D, Chambon P, Yao Z, Ginsberg HN, Pajvani UB. Gamma-secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor. Cell Metabolism, 2018. DOI: 10.1016/j.cmet.2018.02.010 | PubMed

  4. Zhu C, Kim K, Wang X, Bartolome A, Salomao M, Dongiovanni P, Meroni M, Graham MJ, Yates KP, Diehl AM, Schwabe RF, Tabas I, Valenti L, Lavine JE and Pajvani UB. Hepatocyte Notch activation induces liver fibrosis in non-alcoholic steatohepatitis. Science Translational Medicine, 2018. DOI: 10.1126/scitranslmed.aat0344 | PubMed