HGF/HGFR Axis and Fatty Liver Disease

Summary

Principal Investigator: Reza Zarnegar
Abstract: Roughly a quarter of U.S. citizens have steatosis or fat accumulation in their liver cells. The underlying causes of fatty liver (FL) are numerous, but alcohol intake and obesity rank as the most common. Obesity and FL are associated with Metabolic Syndrome (MetSyn) which encompasses a constellation of symptoms indicating that the body has become resistant to the metabolic effects of the hormone insulin. Insulin resistance that develops in the liver as a consequence of obesity is known as non-alcoholic fatty liver disease (NAFLD) and is characterized by the liver's inability to suppress glucose synthesis and to appropriately synthesize and export lipids. NAFLD leads to hepatic fibrosis, cirrhosis and liver cancer in some patients. Our new preliminary data indicate that, in hepatocytes, the insulin receptor (IR) tyrosine kinase crosstalks with the Hepatocyte Growth Factor Receptor (HGFR) tyrosine kinase (also known as Met) through intermolecular tyrosine phosphorylation. We observe that Met and IR interact in the liver and that their direct association is crucial to a proper insulin response. Our data have led us to suggest that, in the absence of Met activity, IR signaling is `sluggish' showing reduced signal output. Taking this concept another step further, we hypothesize that insulin resistance in the liver results at least in part from impaired signaling in the HGF/Met axis. We propose two comprehensive specific aims to test these ideas. In Aim 1, we will analyze the intermolecular interaction, activation and signaling of Met and IR. In Aim 2, we will examine the consequences of Met and IR intermolecular interaction in hepatocytic cells and evaluate their combined contribution to hepatic glucose and fatty acid metabolism utilizing a combination of cell culture and transgenic mouse models. We anticipate that data derived from these kinds of experiments will lead us to describe a new paradigm in insulin signal transduction. It is possible that enhancing Met-IR crosstalk through pharmacologic means will improve insulin resistance which is seminal to the NAFLD and MetSyn phenotype.
Funding Period: 2009-07-01 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism
    Arlee Fafalios
    Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Nat Med 17:1577-84. 2011
  2. pmc Novel Death Defying Domain in Met entraps the active site of caspase-3 and blocks apoptosis in hepatocytes
    Jihong Ma
    Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA
    Hepatology 59:2010-21. 2014

Research Grants

  1. USC Research Center for Liver Disease
    Neil Kaplowitz; Fiscal Year: 2013
  2. LIPIN 1 IN THE REGULATION OF HEPATIC LIPID METABOLISM
    Brian N Finck; Fiscal Year: 2013
  3. Hepatic Lipid Mobilization by Nuclear Hormone Receptors
    Yoon Kwang Lee; Fiscal Year: 2013
  4. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  5. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
  6. Effects of recombinant human leptin in nonalcoholic fatty liver disease (NAFLD)
    Elif Arioglu Oral; Fiscal Year: 2013
  7. Regulation of Bile Acid Synthesis by Nuclear Receptors
    John Y L Chiang; Fiscal Year: 2013
  8. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
  9. Regulation of Liver by Nuclear Ca2+ Signaling
    Michael H Nathanson; Fiscal Year: 2013
  10. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism
    Arlee Fafalios
    Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Nat Med 17:1577-84. 2011
    ..These results provide new insights into the molecular basis of hepatic insulin resistance and suggest that HGF may have therapeutic potential for type 2 diabetes in the clinical setting...
  2. pmc Novel Death Defying Domain in Met entraps the active site of caspase-3 and blocks apoptosis in hepatocytes
    Jihong Ma
    Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA
    Hepatology 59:2010-21. 2014
    ..Studies of both human liver cancer tissues and cell lines uncovered that DDD cleavage and entrapment of caspase-3 by DDD occur in vivo, further proving that this site has physiological and pathophysiological relevance...

Research Grants30

  1. USC Research Center for Liver Disease
    Neil Kaplowitz; Fiscal Year: 2013
    ....
  2. LIPIN 1 IN THE REGULATION OF HEPATIC LIPID METABOLISM
    Brian N Finck; Fiscal Year: 2013
    ..The results f these studies will not only have implications for our understanding of the biology of lipin proteins, but will also provide new insight into the basic molecular regulation of intermediary metabolism. ..
  3. Hepatic Lipid Mobilization by Nuclear Hormone Receptors
    Yoon Kwang Lee; Fiscal Year: 2013
    ....
  4. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  5. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  6. Effects of recombinant human leptin in nonalcoholic fatty liver disease (NAFLD)
    Elif Arioglu Oral; Fiscal Year: 2013
    ..If our hypotheses are correct, 20% of people with fatty liver disease (those with relative leptin deficiency) may derive direct clinical benefit from implications of our research. ..
  7. Regulation of Bile Acid Synthesis by Nuclear Receptors
    John Y L Chiang; Fiscal Year: 2013
    ..The long-term objectives of this research are to elucidate the molecular mechanism of regulation of CYP7A1 and bile acid metabolism, and pathogenesis and treatment of metabolic diseases such as fatty liver disease, diabetes and obesity. ..
  8. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  9. Regulation of Liver by Nuclear Ca2+ Signaling
    Michael H Nathanson; Fiscal Year: 2013
    ..abstract_text> ..
  10. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..