Heme-oxygenase and lipid mediators in obesity and associated cardiometabolic diseases: Therapeutic implications

McClung, John A.; Levy, Lior; García, Víctor; Stec, David E.; Peterson, Stephen J.; Abraham, Nader G.

doi:10.1016/j.pharmthera.2021.107975

Cited by 24 publications

(21 citation statements)

References 406 publications

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“…Our results support the hypothesis that PGC-1α induction in adipocytes leads to HO-1 expression to satisfy its requirement for increased levels of HO-1 activity and to regulate critical aspects of insulin signaling, mitochondrial integrity, anti-inflammatory effects, and adipose tissue browning. The present results indicate and confirm previous reports that the recruitment of HO-1 is essential to mediate the beneficial effects of PGC-1α on the improvement of mitochondrial function, adipocyte browning, vascular tone, and reduced inflammation [ 60 , 61 , 62 ].…”

Section: Discussionsupporting

confidence: 92%

Adipocyte-Specific Expression of PGC1α Promotes Adipocyte Browning and Alleviates Obesity-Induced Metabolic Dysfunction in an HO-1-Dependent Fashion

et al. 2022

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Recent studies suggest that PGC1-α plays a crucial role in mitochondrial and vascular function, yet the physiological significance of PGC1α and HO expression in adipose tissues in the context of obesity-linked vascular dysfunction remains unclear. We studied three groups of six-week-old C57BL/6J male mice: (1) mice fed a normal chow diet; (2) mice fed a high-fat diet (H.F.D.) for 28 weeks, and (3) mice fed a high-fat diet (H.F.D.) for 28 weeks, treated with adipose-specific overexpression of PGC-1α (transgenic-adipocyte-PGC-1α) at week 20, and continued on H.F.D. for weeks 20–28. R.N.A. arrays examined 88 genes involved in adipocyte proliferation and maturation. Blood pressure, tissue fibrosis, fasting glucose, and oxygen consumption were measured, as well as liver steatosis, and the expression levels of metabolic and mitochondrial markers. Obese mice exhibited a marked reduction of PGC1α and developed adipocyte hypertrophy, fibrosis, hepatic steatosis, and decreased mitochondrial respiration. Mice with adipose-specific overexpression of PGC1-α exhibited improvement in HO-1, mitochondrial biogenesis and respiration, with a decrease in fasting glucose, reduced blood pressure and fibrosis, and increased oxygen consumption. PGC-1α led to the upregulated expression of processes associated with the browning of fat tissue, including UCP1, FGF21, and pAMPK signaling, with a reduction in inflammatory adipokines, NOV/CCN3 expression, and TGFβ. These changes required HO-1 expression. The R.N.A. array analysis identified subgroups of genes positively correlated with contributions to the browning of adipose tissue, all dependent on HO-1. Our observations reveal a positive impact of adipose-PGC1-α on distal organ systems, with beneficial effects on HO-1 levels, reversing obesity-linked cardiometabolic disturbances.

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Section: Discussionsupporting

confidence: 92%

Adipocyte-Specific Expression of PGC1α Promotes Adipocyte Browning and Alleviates Obesity-Induced Metabolic Dysfunction in an HO-1-Dependent Fashion

et al. 2022

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“…HO-1 has been shown to reduce NLRP3 inflammasome activity in mice (32); it also reduces visceral fat accumulation, normalizes metabolic profiles, and prevents obesity, thereby reducing cardiovascular and renal complications (7,(33)(34)(35). Notably, these beneficial effects were partly mediated through impacts on the adiponectin-dependent pathway (36,37). Adiponectin is mainly secreted by white adipose tissue; however, its levels are usually lower in the context of obesity and metabolic syndrome, despite adipose accumulation (38).…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin Attenuates Obesity-Related Kidney Dysfunction and NLRP3 Inflammasome Activity Through the HO-1–Adiponectin Axis

Zhang

et al. 2022

Front. Endocrinol.

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Empagliflozin (EMPA) is a novel sodium-glucose cotransporter 2 inhibitor (SGLT2i) that produces protective cardiovascular-renal outcomes in patients with diabetes. However, the effects of EMPA on obesity-related kidney disease have not been determined. The heme oxygenase-1 (HO-1)–adiponectin axis is an essential antioxidant system with anti-apoptotic and anti-inflammatory properties. This study explored whether EMPA improves obesity-related kidney disease through regulation of the renal HO-1-mediated adiponectin axis. C57BL/6J mice were assigned to control, high-fat diet (HFD) groups, and EMPA (10 mg/kg) groups. HFD mice showed metabolic abnormality and renal injury, including increased urinary albumin excretion, morphologic changes, and lipid accumulation. EMPA treatment improved metabolic disorders and attenuated lipotoxicity-induced renal injury. Furthermore, EMPA treatment ameliorated renal NLRP3 inflammasome activity and upregulated the HO-1–adiponectin axis. Our findings indicate that EMPA improves obesity-related kidney disease through reduction of NLRP3 inflammasome activity and upregulation of the HO-1–adiponectin axis, suggesting a novel mechanism for SGLT2i-mediated renal protection in obesity.

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“…The release of bilirubin by ECs may also curb the accelerated rate of atherosclerosis in diabetes through its impact on adhesion molecule expression as well as cholesterol metabolism [ 57 , 58 ]. Intriguingly, bilirubin improves renal blood flow, renal vascular resistance, and glomerular filtration rate, and this may underlie the reduced risk for kidney failure in patients with T2DM and nephropathy receiving canagliflozin [ 59 , 60 , 61 , 62 ]. Recently, bilirubin was demonstrated to be a potent activator of peroxisome-proliferator-activated receptor-α (PPARα), triggering the transcription of a host of PPARα target genes that regulate whole-body energy homeostasis, including fibroblast growth factor 21 [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

Canagliflozin Inhibits Human Endothelial Cell Inflammation through the Induction of Heme Oxygenase-1

Peyton

Behnammanesh

Durante

et al. 2022

IJMS

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Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). Studies have also shown that canagliflozin directly acts on endothelial cells (ECs). Since heme oxygenase-1 (HO-1) is an established modulator of EC function, we investigated if canagliflozin regulates the endothelial expression of HO-1, and if this enzyme influences the biological actions of canagliflozin in these cells. Treatment of human ECs with canagliflozin stimulated a concentration- and time-dependent increase in HO-1 that was associated with a significant increase in HO activity. Canagliflozin also evoked a concentration-dependent blockade of EC proliferation, DNA synthesis, and migration that was unaffected by inhibition of HO-1 activity and/or expression. Exposure of ECs to a diabetic environment increased the adhesion of monocytes to ECs, and this was attenuated by canagliflozin. Knockdown of HO-1 reduced the anti-inflammatory effect of canagliflozin which was restored by bilirubin but not carbon monoxide. In conclusion, this study identified canagliflozin as a novel inducer of HO-1 in human ECs. It also found that HO-1-derived bilirubin contributed to the anti-inflammatory action of canagliflozin, but not the anti-proliferative and antimigratory effects of the drug. The ability of canagliflozin to regulate HO-1 expression and EC function may contribute to the clinical profile of the drug.

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Heme-oxygenase and lipid mediators in obesity and associated cardiometabolic diseases: Therapeutic implications

Cited by 24 publications

References 406 publications

Adipocyte-Specific Expression of PGC1α Promotes Adipocyte Browning and Alleviates Obesity-Induced Metabolic Dysfunction in an HO-1-Dependent Fashion

Adipocyte-Specific Expression of PGC1α Promotes Adipocyte Browning and Alleviates Obesity-Induced Metabolic Dysfunction in an HO-1-Dependent Fashion

Empagliflozin Attenuates Obesity-Related Kidney Dysfunction and NLRP3 Inflammasome Activity Through the HO-1–Adiponectin Axis

Canagliflozin Inhibits Human Endothelial Cell Inflammation through the Induction of Heme Oxygenase-1

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