AMPK activator, AICAR, inhibits palmitate-induced apoptosis in osteoblast.
Osteoblast apoptosis reduces bone mineral density. Apoptosis can be induced in a variety of cells by palmitate, which is one of the most common saturated fatty acids in dietary fat. The AMPK activator, AICAR, has been shown to inhibit palmitate-induced apoptosis. However, the role of palmitate in osteoblast apoptosis is currently unknown. This study examined whether palmitate could induce apoptosis in osteoblasts, and if so, whether AICAR could alleviate palmitate-induced apoptosis. Palmitate reduced cell survival and induced apoptosis in a dose- and time-dependent manner in human fetal osteoblasts (hFOB) 1.19. While the long-chain acyl-CoA synthetase inhibitor, triacsin C, inhibited palmitate-induced apoptosis, anti-oxidants and ceramide synthesis inhibitors did not attenuate the apoptosis. AICAR prevented palmitate-induced apoptosis and the inhibition of AICAR-mediated increase in fatty acid oxidation by etomoxir did not affect the prevention of apoptosis by AICAR. Constitutively-active AMPK also inhibited palmitate-induced apoptosis. Treatment with an AMPK inhibitor (compound C) and a dominant-negative AMPK adenovirus suppressed the inhibitory effect of AICAR on apoptosis. Palmitate impaired the activation of ERK by fetal bovine serum, which was blocked by AICAR. Moreover, AICAR increased ERK activation, and ERK inhibitors, PD98059 and U0126, as well as a dominant-negative MEK1, abolished the inhibitory effect of AICAR on palmitate-induced apoptosis. AICAR also inhibited palmitate-induced apoptosis in osteoblastic differentiated cells from human bone marrow, which was accompanied by recovered ERK activity. These results suggest that palmitate induces apoptosis in osteoblasts through the impaired activation of ERK, and the activation of AMPK inhibits palmitate-induced apoptosis by activating ERK.
Kim
Ji-Eun
JE
Department of Physiology, College of Medicine, Yeungnam University, Daegu, South Korea; Aging-associated Vascular Disease Research Center, Yeungnam University, Daegu, South Korea.
Ahn
Myun-Whan
MW
Department of Orthopedics, College of Medicine, Yeungnam University, Daegu, South Korea.
Baek
Suk-Hwan
SH
Aging-associated Vascular Disease Research Center, Yeungnam University, Daegu, South Korea; Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, South Korea.
Lee
In Kyu
IK
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Kim
Yong-Woon
YW
Department of Physiology, College of Medicine, Yeungnam University, Daegu, South Korea.
Kim
Jong-Yeon
JY
Department of Physiology, College of Medicine, Yeungnam University, Daegu, South Korea.
Dan
Jin-Myoung
JM
Department of Orthopedics, College of Medicine, Pochun Cha University, Kumi, South Korea.
Park
So-Young
SY
Department of Physiology, College of Medicine, Yeungnam University, Daegu, South Korea; Aging-associated Vascular Disease Research Center, Yeungnam University, Daegu, South Korea. Electronic address: sypark@med.yu.ac.kr.
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002070:Butadienes / Q000494:pharmacology; D002210:Caprylates / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology; D037341:Fumonisins / Q000494:pharmacology; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology*; D010168:Palmitates / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D013997:Time Factors
D000975:Antioxidants; D002070:Butadienes; D002210:Caprylates; D002518:Ceramides; D020536:Enzyme Activators; D004852:Epoxy Compounds; D005419:Flavonoids; D037341:Fumonisins; D009097:Multienzyme Complexes; D009570:Nitriles; D010168:Palmitates; D012265:Ribonucleotides; C113580:U 0126; D000620:Aminoimidazole Carboxamide; C056933:fumonisin B1; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; C054207:etomoxir; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one