title: 4-Hydroxynonenal differentially regulates adiponectin gene expression and secretion via activating PPARγ and accelerating ubiquitin-proteasome degradation.
abstract: Although well-established, the underlying mechanisms involved in obesity-related plasma adiponectin decline remain elusive. Oxidative stress is associated with obesity and insulin resistance and considered to contribute to the progression toward obesity-related metabolic disorders. In this study, we investigated the effects of 4-hydroxynonenal (4-HNE), the most abundant lipid peroxidation end product, on adiponectin production and its potential implication in obesity-related adiponectin decrease. Long-term high-fat diet feeding led to obesity in mouse, accompanied by decreased plasma adiponectin and increased adipose tissue 4-HNE content. Exposure of adipocytes to exogenous 4-HNE resulted in decreased adiponectin secretion in a dose-dependent manner, which was consistent with significantly decreased intracellular adiponectin protein abundance. In contrast, adiponectin gene expression was significantly elevated by 4-HNE treatment, which was concomitant with increased peroxisome proliferator-activated receptor gamma (PPAR-γ) gene expression and transactivity. The effect was abolished by T0070907, a PPAR-γ antagonist, suggesting that PPAR-γ activation plays a critical role in this process. To gain insight into mechanisms involved in adiponectin protein decrease, we examined the effects of 4-HNE on adiponectin protein degradation. Cycloheximide (CHX)-chase assay revealed that 4-HNE exposure accelerated adiponectin protein degradation, which was prevented by MG132, a potent proteasome inhibitor. Immunoprecipitation assay showed that 4-HNE exposure increased ubiquitinated adiponectin protein levels. These data altogether indicated that 4-HNE enhanced adiponectin protein degradation via ubiquitin-proteasome system. Finally, we demonstrated that supplementation of HF diet with betaine, an antioxidant and methyl donor, alleviated high-fat-induced adipose tissue 4-HNE increase and attenuated plasma adiponectin decline. Taken together, our findings suggest that the lipid peroxidation product 4-HNE can differentially regulates adiponectin gene expression and protein abundance and may play a mechanistic role in obesity-related plasma adiponectin decline.
authors.affiliation: Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Dou
authors.forename: Dongfang
authors.initials: D
authors.lastname: Gu
authors.forename: Chen
authors.initials: C
authors.lastname: Shen
authors.forename: Tong
authors.initials: T
authors.lastname: Yao
authors.forename: Van
authors.initials: V
authors.lastname: Nguyen
authors.forename: Carol
authors.initials: C
authors.lastname: Braunschweig
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Song
mesh_terms: D041721:3T3-L1 Cells; D052242:Adiponectin / Q000097:blood* / Q000235:genetics; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D007333:Insulin Resistance; D007976:Leupeptins / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood* / Q000209:etiology; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D059748:Proteolysis; D011725:Pyridines / Q000494:pharmacology; D025801:Ubiquitin / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D000447:Aldehydes; D001549:Benzamides; D007976:Leupeptins; D047495:PPAR gamma; D061988:Proteasome Inhibitors; D011725:Pyridines; C458508:T 0070907; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; C027576:4-hydroxy-2-nonenal; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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