Utpal Pajvani, MD, PhD

The overarching research theme of the Pajvani lab is to uncouple obesity from its metabolic and neoplastic complications in order to expose therapeutically tractable pathways in prevalent and morbid obesity-related diseases. 

Notch signaling has proven necessary for normal development across species, but until recently there was limited data on a potential post-development role. The Pajvani lab established the concept that Notch activity is a maladaptive response to obesity, leading to metabolic and neoplastic complications. In the liver, Notch activity is causal to the hepatic insulin resistance that characterizes type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). NASH has no pharmacotherapy, leading to a huge unmet need. The dearth of treatment options is due to incomplete understanding of molecular drivers of NASH-induced liver fibrosis, the major determinant of mortality in these patients. NASH is also the fastest growing reason for hepatocellular carcinoma (HCC), a catastrophic diagnosis with poor treatment options. The Pajvani lab found that Notch catalyzes each transition step in this process: 1) Notch activity is associated with T2D and NASH in patients; 2) Hepatocyte-specific Notch loss-of-function reduced fibrosis in mice fed a NASH-inducing diet; and 3) Hepatocyte-specific Notch gain-of-function exacerbated fibrosis and even induced HCC in male and female mice.  

While conducting these studies, in a global survey of tissues from Notch reporter mice, the Pajvani lab detected ongoing Notch activity in a small subset of pancreatic β cells, specifically increased by hyperglycemia or high-fat diet (HFD) feeding, and in islets isolated from patients with T2D. To query the repercussions of this unexpected β cell Notch activity, the Pajvani lab created inducible, β cell-specific Notch loss-of-function mice, indistinguishable from Cre- controls when fed normal chow, but protected from HFD-induced glucose intolerance. Conversely, Notch gain-of-function mice show the opposite phenotype – impaired β cell maturity, disrupted islet architecture, and exacerbated glucose intolerance. The Pajvani lab is now testing mechanisms of “re-activated” Notch activity in β cells, and developing inhibitors for possible application to patients with T2D and NASH.

Recent Publications

  • 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 and Pajvani UB. Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis. 2021. Science Translational Medicine 13 doi: 10.1126/scitranslmed.abe1692.
  • 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. 2020. J. Hepatology doi: 10.1016/j.jhep.2020.09.032.
  • Bartolome A, Zhu C, Sussel L, Pajvani UB. Notch signaling dynamically regulates adult β cell proliferation and maturity. 2019. Journal of Clinical Investigation doi: 10.1172/JCI98098. 
  • 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. 2018. Cell Metabolism 27, 816-827.

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