Novel proapoptotic effect of hepatocyte growth factor: synergy with palmitate to cause pancreatic {beta}-cell apoptosis

Endocrinology. 2010 Apr;151(4):1487-98. doi: 10.1210/en.2009-0975. Epub 2010 Feb 22.


Increasing evidence suggests that elevation of plasma fatty acids that often accompanies insulin resistance contributes to beta-cell insufficiency in obesity-related type 2 diabetes. Circulating levels of hepatocyte growth factor (HGF) are increased in humans with metabolic syndrome and obesity. HGF is known to protect beta-cells against streptozotocin and during islet engraftment. However, whether HGF is a beta-cell prosurvival factor in situations of excessive lipid supply has not been deciphered. Mice overexpressing HGF in the beta-cell [rat insulin type II promoter (RIP)-HGF transgenic mice] fed with standard chow display improved glucose homeostasis and increased beta-cell mass and proliferation compared with normal littermates. However, after 15 wk of high-fat feeding, glucose homeostasis and beta-cell expansion and proliferation are indistinguishable between normal and transgenic mice. Interestingly, RIP-HGF transgenic mouse beta-cells and normal beta-cells treated with HGF display increased sensitivity to palmitate-mediated apoptosis in vitro. Palmitate completely eliminates Akt and Bad phosphorylation in RIP-HGF transgenic mouse islets. HGF-overexpressing islets also show significantly decreased AMP-activated protein kinase-alpha and acetyl-coenzyme A carboxylase phosphorylation, diminished fatty acid oxidation, increased serine palmitoyltransferase expression, and enhanced ceramide formation compared with normal islets. Importantly, human islets overexpressing HGF also display increased beta-cell apoptosis in the presence of palmitate. Treatment of both mouse and human islet cells with the de novo ceramide synthesis inhibitors myriocin and fumonisin B1 abrogates beta-cell apoptosis induced by HGF and palmitate. Collectively, these studies indicate that HGF can be detrimental for beta-cell survival in an environment with excessive fatty acid supply.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Apoptosis / physiology*
  • Blood Glucose / metabolism
  • Blotting, Western
  • Cell Proliferation
  • Cell Size
  • Cells, Cultured
  • Ceramides / analysis
  • Dietary Fats / administration & dosage
  • Fatty Acids / metabolism*
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Insulin-Secreting Cells / chemistry
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology*
  • Mice
  • Mice, Transgenic
  • Palmitic Acid / metabolism*
  • Palmitic Acid / pharmacology
  • Pancreas / metabolism
  • Pancreas / pathology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • bcl-Associated Death Protein / metabolism


  • Bad protein, mouse
  • Blood Glucose
  • Ceramides
  • Dietary Fats
  • Fatty Acids
  • bcl-Associated Death Protein
  • Palmitic Acid
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-akt