Insulin protects liver cells from saturated fatty acid-induced apoptosis via inhibition of c-Jun NH2 terminal kinase activity.

Abstract

Hepatocyte apoptosis is increased in patients with nonalcoholic steatohepatitis and correlates with disease severity. Long-chain saturated fatty acids, such as palmitate and stearate, induce apoptosis in liver cells. The present study examined insulin-mediated protection against saturated fatty acid-induced apoptosis in the rat hepatoma cell line, H4IIE, and primary rat hepatocytes. Cells were provided a control media (no fatty acids) or the same media containing 250 micromol/liter of albumin-bound oleate or palmitate for 16 h. Insulin concentrations were 0, 1, 10, or 100 nmol/liter (n=4-6/treatment). Palmitate, but not oleate, activated caspase-3 and induced DNA fragmentation in the absence of insulin. Insulin reduced palmitate-mediated activation of caspase-3 and DNA fragmentation in a dose-dependent manner. Phosphatidylinositol 3-kinase inhibitors abolished these effects of insulin. Insulin-mediated inhibition of palmitate-induced apoptosis was not due to an augmentation in the unfolded protein response or increased expression of genes encoding the inhibitor of apoptosis proteins, inhibitor of apoptosis protein-2 and X-linked mammalian inhibitor of apoptosis protein. Palmitate, but not oleate, increased c-Jun NH2 terminal kinase activity in the absence of insulin. Insulin or SP600125, a chemical inhibitor of c-Jun NH2 terminal kinase, blocked palmitate-mediated activation of c-Jun NH2 terminal kinase and reduced apoptosis. These data suggest that insulin is an important determinant of saturated fatty acid-induced apoptosis in liver cells and may have implications for fatty acid-mediated liver cell injury in insulin-deficient and/or -resistant states.

• Authors: M J Pagliassotti, Y Wei, D Wang
• Journal: Endocrinology (Endocrinology) Vol. 148 Issue 7 Pg. 3338-45 (Jul 2007) ISSN: 0013-7227 [Print] United States
• PMID: 17431009 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Androstadienes
• Anthracenes
• Chromones
• Fatty Acids
• Inhibitor of Apoptosis Proteins
• Insulin
• Morpholines
• Palmitates
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• pyrazolanthrone
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Thapsigargin
• JNK Mitogen-Activated Protein Kinases
• Caspase 3
• Wortmannin

Topics

• Androstadienes (pharmacology)
• Animals
• Anthracenes (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cells, Cultured
• Chromones (pharmacology)
• DNA Fragmentation (drug effects)
• Enzyme Activation (drug effects)
• Fatty Acids (pharmacology)
• Female
• Hepatocytes (cytology, drug effects, metabolism)
• Immunoblotting
• Inhibitor of Apoptosis Proteins (genetics, metabolism)
• Insulin (pharmacology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Morpholines (pharmacology)
• Palmitates (pharmacology)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Rats
• Rats, Wistar
• Reverse Transcriptase Polymerase Chain Reaction
• Thapsigargin (pharmacology)
• Wortmannin