Novel proapoptotic effect of hepatocyte growth factor: synergy with palmitate to cause pancreatic {beta}-cell apoptosis.
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.
González-Pertusa
José A
JA
Division of Endocrinology, University of Pittsburgh, 200 Lothrop Street, BST-E1140, Pittsburgh, Pennsylvania 15261, USA.
Dubé
John
J
Valle
Shelley R
SR
Rosa
Taylor C
TC
Takane
Karen K
KK
Mellado-Gil
José M
JM
Perdomo
Germán
G
Vasavada
Rupangi C
RC
García-Ocaña
Adolfo
A
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D048429:Cell Size; D002478:Cells, Cultured; D002518:Ceramides / Q000032:analysis; D004041:Dietary Fats / Q000008:administration & dosage; D005227:Fatty Acids / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D050417:Insulin-Secreting Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D019308:Palmitic Acid / Q000378:metabolism* / Q000494:pharmacology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism
C494820:Bad protein, mouse; D001786:Blood Glucose; D002518:Ceramides; D004041:Dietary Fats; D005227:Fatty Acids; D051025:bcl-Associated Death Protein; D019308:Palmitic Acid; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt