Why Notch?
Notch signaling is a highly conserved cell signaling system involved in embryonic development. The canonical pathway involves a ligand-receptor interaction mediated by transmembrane-receptor cleavage and nuclear recruitment of multiple transcription factors & co-activators. Under physiologic conditions, it is tightly regulated to direct cellular differentiation, proliferation, and apoptosis.
While aberrant Notch signaling has been implicated in many types of cancer, we have uncovered pathological reactivation of Notch signaling in obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). Following where the data led us, we currently focus on Notch's role in liver injury & tumor growth, glucose production, lipogenesis, and β cell function.
Schematic created using BioRender.com.
Current Research
GLUCOSE HOMEOSTASIS
Maladaptive Notch reactivation in obesity-induced glucose homeostasis.
NAFLD & NASH
Notch as a causal factor for NASH, NAFLD, and dyslipidemia.
LIPID HOMEOSTASIS
Notch signaling as a modulator of de novo lipogenesis, liver inflammation, and fibrosis.
Selected Publications
2018 — Present | 2015 — 2017 | 2011 — 2014 | ALL
2018 — PRESENT
Steinman JB, Salomao MA, Pajvani UB. Zonation in NASH - A key paradigm for understanding pathophysiology and clinical outcomes. Liver International, 2021. DOI: doi.org/10.1111/liv.15025 | PubMed
Yu J, Zhu C, Wang X, Kim K, Bartolome A, Dongiovanni P, Yates KP, Valenti L, Carrer M, Sadowski T, Qiang L, Tabas I, Lavine JE, Pajvani UB. Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis. Science Translational Medicine, 2021. DOI: doi.org/10.1126/scitranslmed.abe1692 | PubMed
Kim K, Kang JK, Jung YH, Lee SB, Rametta R, Dongiovanni P, Valenti L, Pajvani UB. Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver. Nature Communications, 2021. DOI: doi.org/10.1038/s41467-021-22106-2 | PubMed
Zhu C, Tabas I, Schwabe RF, Pajvani UB. Maladaptive regeneration - the reawakening of developmental pathways in NASH and fibrosis. Nature Rev Gastro Hep, 2021.DOI: doi: 10.1038/s41575-020-00365-6 | PubMed
Zhu C, Ho Y-J, Salomao MA, Dapito DH, Bartolome A, Schwabe RF, Lee, J-S, Lowe SW, Pajvani UB. Notch activity determines a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features. J Hepatology, 2020. DOI: doi.org/10.1016/j.jhep.2020.09.032 | PubMed
Richter LR, Wan Q, Wen D, Zhang Y, Yu J, Kang JK, McKinnon EL, Gu Z, Qiang L, Pajvani UB. Targeted delivery of Notch inhibitor attenuates obesity-induced glucose intolerance and liver fibrosis. ACS Nano, 2020. DOI: 10.1021/acsnano.0c01007 | PubMed
Kim K, Yu J, Kang JK, Morrow JP, Pajvani UB. Liver-selective γ-secretase inhibition ameliorates diet-induced hepatic steatosis, dyslipidemia and atherosclerosis. Biochem Biophys Research Comm, 2020. DOI: 10.1016/j.bbrc.2020.04.157 | PubMed
Bartolome A, Zhu C, Sussel L, Pajvani UB. Notch signaling dynamically regulates adult β cell proliferation and maturity. J Clin Invest., 2019. DOI: 10.1172/JCI98098 | PubMed
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
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
2015 — 2017
Bartolome A, Garcia-Aguilar A, Ashara S-I, Kido Y, Guillen C, Pajvani UB, Benito M. MTORC1 regulates both general autophagy and mitophagy induction after oxidative phosphorylation uncoupling. Molecular Cell Biology, 2017. DOI: 10.1128/MCB.00441-17 | PubMed
Kim K, Ryu D, Dongiovanni P, Ozcan L, Nayak S, Ueberheide B, Valenti L, Auwerx J, Pajvani UB. Degradation of PHLPP2 by KCTD17, via a Glucagon-dependent pathway, promotes hepatic steatosis. Gastroenterology, 2017. DOI: 10.1053/j.gastro.2017.08.039 | PubMed
Kim K, Pajvani UB. “Free” Raptor - a novel regulator of metabolism. Cell Cycle, 2016. DOI: 10.1080/15384101.2016.1159835 | PubMed
Kim K, Hayden M, Qiang L, Sparling D, Purcell N, Pajvani UB. mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2. Nature Communications, 2016. DOI: 10.1038/ncomms10255 | PubMed
Sparling DP, Yu J, Kim K, Zhu C, Brachs S, Birkenfeld AL, Pajvani UB. Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity. Molecular Metabolism, 2015. DOI: 10.1016/j.molmet.2015.11.006 | PubMed
Pajvani UB, Accili D. The new biology of diabetes. Diabetologia, 2015. DOI: 10.1007/s00125-015-3722-5 | PubMed
2011 — 2014
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
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
Pajvani UB, Shawber CJ, Samuel VT, Birkenfeld AL, Shulman GI, Kitajewski J, Accili D. Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nature Medicine, 2011. DOI: 10.1038/nm.2378 | PubMed