Linoleic acid stimulates gluconeogenesis via Ca2+/PLC, cPLA2, and PPAR pathways through GPR40 in primary cultured chicken hepatocytes.
Fatty acids serve vital functions as sources of energy, building materials for cellular structures, and modulators of physiological responses. Therefore, this study examined the effect of linoleic acid on glucose production and its related signal pathways in primary cultured chicken hepatocytes. Linoleic acid (double-unsaturated, long chain) increased glucose production in a dose (> or =10(-4) M)- and time (> or =8 h)-dependent manner. Both oleic acid (monounsaturated, long chain) and palmitic acid (saturated, long chain) also increased glucose production, whereas caproic acid (saturated, short chain) failed to increase glucose production. Linoleic acid increased G protein-coupled receptor 40 (GPR40; also known as free fatty acid receptor-1) protein expression and glucose production that was blocked by GPR40-specific small interfering RNA. Linoleic acid increased intracellular calcium concentration, which was blocked by EGTA (extracellular calcium chelator)/BAPTA-AM (intracellular calcium chelator), U-73122 (phospholipase C inhibitor), nifedipine, or methoxyverapamil (L-type calcium channel blockers). Linoleic acid increased cytosolic phospholipase A(2) (cPLA(2)) phosphorylation and the release of [(3)H]-labeled arachidonic acid. Moreover, linoleic acid increased the level of cyclooxygenase-2 (COX-2) protein expression, which stimulated the synthesis of prostaglandin E(2) (PGE(2)). The increase in PGE(2) production subsequently stimulated peroxisome proliferator-activated receptor (PPAR) expression, and MK-886 (PPAR-alpha antagonist) and GW-9662 (PPAR-delta antagonist) inhibited glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. In addition, linoleic acid-induced glucose production was blocked by inhibition of extracellular and intracellular calcium, cPLA(2), COX-2, or PPAR pathways. In conclusion, linoleic acid promoted glucose production via Ca(2+)/PLC, cPLA(2)/COX-2, and PPAR pathways through GPR40 in primary cultured chicken hepatocytes.
Suh
Han Na
HN
Dept. of Veterinary Physiology, Chonnam National University, Gwangju 500-757, Korea.
Huong
Huang Thi
HT
Song
Chang Hun
CH
Lee
Jang Hern
JH
Han
Ho Jae
HJ
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002645:Chickens; D004797:Enzyme-Linked Immunosorbent Assay; D005943:Gluconeogenesis / Q000502:physiology*; D054513:Group IV Phospholipases A2 / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D019787:Linoleic Acid / Q000378:metabolism*; D008297:Male; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism
D047492:Peroxisome Proliferator-Activated Receptors; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D019787:Linoleic Acid; D054513:Group IV Phospholipases A2; D010738:Type C Phospholipases; D002118:Calcium