title: PKC-ALDH2 Pathway Plays a Novel Role in Adipocyte Differentiation.
abstract: The ALDH2 gene encodes the mitochondrial aldehyde dehydrogenase 2 (ALDH2), a critical enzyme involved in ethanol clearance through acetaldehyde metabolism. ALDH2 also catalyzes the metabolism of other bioreactive aldehydes, including propionaldehyde, butyraldehyde, and 4-hydroxykenals (4-HNE). Increased levels of 4-HNE in adipose tissue positively correlate with obesity and insulin resistance. However, it remains unclear whether ALDH2 is involved in regulation of adipocyte differentiation. Here, we found that ALDH2 protein levels were lower in white adipose tissue of high-fat diet-fed mice and ob/ob mice relative to lean mice. Knockdown of ALDH2 expression in 3T3-L1 preadipocytes caused an increase in intracellular 4-HNE, thereby attenuated adipocyte differentiation. By contrast, an ALDH2 activator, Alda-1, significantly accelerated adipogenesis, which was accompanied by an increase in adipogenic gene expression. Consistently, adipogenesis was reduced when protein kinase C ε (PKCε), an ALDH2 phosphorylating activator, was silenced in 3T3-L1 preadipocytes, whereas treatment with a PKCε agonist in 3T3-L1 preadipocytes enhanced adipogenesis. Whole-genome microarray profiling of Alda-1-treated cells demonstrated several upregulated transcripts encoding proteins involved in metabolism and the majority of these transcripts are for proteins involved in PPAR signaling pathways. Furthermore, PKCε-ALDH2 interaction alleviates 4-HNE induced aberrant PPARγ regulation on adipogenesis. Taken together, these results demonstrate that ALDH2 activation enhances adipogenesis and signaling pathways involving PPARγ. Thus, activation of PKCε-ALDH2 regulatory axis may be a therapeutic target for treating obesity and type 2 diabetes.
authors: Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan.
authors: Yu-Hsiang
authors: YH
authors: Yu
authors: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Pei-Ru
authors: PR
authors: Liao
authors: Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Chien-Jung
authors: CJ
authors: Guo
authors: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, 94305, United States of America.
authors: Che-Hong
authors: CH
authors: Chen
authors: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, 94305, United States of America.
authors: Daria
authors: D
authors: Mochly-Rosen
authors: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Lee-Ming
authors: LM
authors: Chuang
mesh_terms: D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000166:cytology* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D020869:Gene Expression Profiling; D051379:Mice; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000235:genetics; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000447:Aldehydes; D001549:Benzamides; D052117:Benzodioxoles; C531525:N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; D047495:PPAR gamma; C515029:ALDH2 protein, mouse; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C497256:Prkce protein, mouse; D051744:Protein Kinase C-epsilon; C027576:4-hydroxy-2-nonenal