HIF regulation of Ammonia Processing and Fibrosis in MASLD/MASH

PROJECT SUMMARY/ABSTRACT
Steatotic liver disease (SLD) prevalence in just the United States is estimated to upwards of a quarter of the
population. It ranges in presentation from simple Hepatic Steatosis without evidence of liver injury to
development of inflammation and fibrosis (Metabolic Associated Steatohepatitis; MASH). Those individuals that
develop MASH have increased risk of progression to advanced fibrosis and ultimately cirrhosis. Understanding
the cellular and molecular mechanisms of the transition from simple steatosis to inflammation and fibrosis is
needed. Recent work has shown that MASH leads to high level of hepatic and systemic ammonia. Moreover,
there is mounting evidence that ammonia can contribute to the progression of MASH. Ammonia levels are
detoxified through the urea cycle. The liver is the major site of ammonia detoxification and consistent with the
increase in ammonia in MASLD, urea cycle genes are significantly decreased in MASLD. However, the
molecular mechanism driving the metabolic reprogramming to alter liver ammonia is unclear. Preliminary
studies have implicated the hypoxia-inducible factor (HIF) pathway in the development of liver steatosis and
fibrosis. I show that activation of hepatocyte HIF2a (but not HIF1a) signaling decrease urea cycle genes,
increases ammonia levels, steatosis, inflammation, and fibrosis. Therefore, I hypothesize that HIF2α
exacerbates liver injury and dysfunction by disrupting urea cycle metabolism, resulting in steatosis,
and promoting an inflammatory and profibrotic response. To test this hypothesis, I propose two Aims: 1)
To understand how dysregulation of HIF signaling drives altered hepatocyte gene expression and metabolism.
Hepatic nuclear factor (HNF)4α is the master transcription factor for the regulation of urea cycle genes. I will
understand the crosstalk of HIF2α and HNF4α signaling. 2) Define if inhibition of HIF2α is a viable target for
clinical intervention in the progression to advanced fibrosis/cirrhosis. Recently a clinically relevant on-target
HIF2a, beltifuzan was approved for clear cell renal carcinomas. I will test the role of beltifuzan in preclinical
models of MASH. The proposed research seeks to understand the role of HIF signaling in the development of
steatosis and fibrosis that if left unabated can progress end stage liver disease and to the sequalae that drive
the significant morbidity and mortality of the disease.

Grant Number: 1F32DK142455-01A1
NIH Institute/Center: NIH
Principal Investigator: Marc Cantwell