Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis

Abstract

ObjectiveWhen molecular drivers of healthy adipogenesis are perturbed, this can cause hepatic steatosis. The role of arachidonic acid (AA) and its downstream enzymatic cascades, such as cyclooxygenase, in adipogenesis is well established. The exact contribution of the P450 epoxygenase pathway, however, remains to be established. Enzymes belonging to this pathway are mainly encoded by the CYP2J locus which shows extensive allelic expansion in mice. Here we aimed to establish the role of endogenous epoxygenase during adipogenesis under homeostatic and metabolic stress conditions.MethodsWe took advantage of the simpler genetic architecture of the Cyp2j locus in the rat and used a Cyp2j4 (orthologue of human CYP2J2) knockout rat in two models of metabolic dysfunction: physiological aging and cafeteria diet (CAF). The phenotyping of Cyp2j4−/− rats under CAF was integrated with proteomics (LC-MS/MS) and lipidomics (LC-MS) analyses in the liver and the adipose tissue.ResultsWe report that Cyp2j4 deletion causes adipocyte dysfunction under metabolic challenges. This is characterized by (i) down-regulation of white adipose tissue (WAT) PPARγ and C/EBPα, (ii) adipocyte hypertrophy, (iii) extracellular matrix remodeling, and (iv) alternative usage of AA pathway. Specifically, in Cyp2j4−/− rats treated with a cafeteria diet, the dysfunctional adipogenesis is accompanied by exacerbated weight gain, hepatic lipid accumulation, and dysregulated gluconeogenesis.ConclusionThese results suggest that AA epoxygenases are essential regulators of healthy adipogenesis. Our results uncover their synergistic role in fine-tuning AA pathway in obesity-mediated hepatic steatosis.

Cyp2j5-Gene Deletion Affects on Acetylcholine and Adenosine-Induced Relaxation in Mice: Role of Angiotensin-II and CYP-Epoxygenase Inhibitor

“…CYP450-epoxygenase (CYP2J2) polymorphisms have been reported in different populations related to its role in cardiovascular function, including hypertension (Lee et al, 2007;Feng et al, 2008;Fava et al, 2010;Jie et al, 2010;Wang et al, 2010;Zordoky and El-Kadi, 2010;Xu et al, 2011). The Cyp2j5-epoxygenase in mouse (chromosome-4) appears to be as important as CYP2J2-epoxygenase in human (chromosome-1) and CYP2J4 in rat (chromosome-5) (Olona et al, 2018). Variations in soluble epoxide hydrolase and w-hydroxylase genes in human population also alter the risk of coronary heart disease, ischemic stroke, restenosis, diabetes heart, heart failure, ischemic stroke in Caucasians, Chinese, and in the African Americans with hypertension (Lee et al, 2006;Burdon et al, 2008;Monti et al, 2008;Kullmann et al, 2009;Fava et al, 2010;Zordoky and El-Kadi, 2010).…”

Mechanism of Dyslipidemia in Obesity—Unique Regulation of Ileal Villus Cell Brush Border Membrane Sodium–Bile Acid Cotransport

“…For this study, an ASBT antibody reactive to rat, mouse, and human samples was used (bs-23146R, Bioss Antibodies Inc., Woburn, MA, USA) to detect ASBT protein expression. The following antibodies were used to detect the expression of the specific proteins: Farnesoid X receptor: FXR, sc-25309, Santa Cruz Biotechnology, Inc., Dallas, TX, USA [40,41]; ileal bile-acid-binding protein: ILBABP, AP26370PU-N, OriGene Global, Rockville, MD, USA [42]; organic solute transporter alpha: OSTα, SAB1306154, Sigma-Aldrich Corporation, St. Louis, MO, USA; and Ezrin: MA5-13862, Invitrogen Life Technologies, Carlsbad, CA, USA [43,44]. All the HRP-conjugated secondary antibodies were obtained from Abcam (Abcam PLC, Cambridge, MA, USA).…”

Genetic Loci and Metabolic States Associated With Murine Epigenetic Aging

“…The more compelling evidence is for the cytochrome P450 genes, which are both positional candidates, as well as expression correlates at the transcriptomic and proteomic levels. These genes have high expression in liver, and have major downstream impact on metabolism 52–54 . One caveat is that these CYP genes are part of a gene cluster in Eaaq19 that includes transcripts with cis -eQTLs (e.g., Cyp2c66 , Cyp2c39 , Cyp2c68 ), and the tight clustering of the genes, and proximity of trait QTL and eQTLs may result in tight co-expression due to linkage disequilibrium 55 .…”