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Obesity in a model of gpx4 haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathy.

Katunga LA, Gudimella P, Efird JT, Abernathy S, Mattox TA, Beatty C, Darden TM, Thayne KA, Alwair H, Kypson AP, Virag JA, Anderson EJ - Mol Metab (2015)

Bottom Line: Biochemical and immuno-histological analysis was performed in heart and liver at termination of study, and mitochondrial function was analyzed in heart.Mitochondrial dysfunction manifesting as decreased fat oxidation capacity and increased reactive oxygen species was also present in obese GPx4(+/-) but not WT hearts, along with up-regulation of pro-inflammatory and pro-fibrotic genes.Patients with diabetes and hyperglycemia exhibited significantly less GPx4 enzyme and greater HNE-adducts in their hearts, compared with age-matched non-diabetic patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology & Toxicology, East Carolina University, Greenville, NC, United States ; Department of Public Health, East Carolina University, Greenville, NC, United States.

ABSTRACT

Objective: Lipid peroxides and their reactive aldehyde derivatives (LPPs) have been linked to obesity-related pathologies, but whether they have a causal role has remained unclear. Glutathione peroxidase 4 (GPx4) is a selenoenzyme that selectively neutralizes lipid hydroperoxides, and human gpx4 gene variants have been associated with obesity and cardiovascular disease in epidemiological studies. This study tested the hypothesis that LPPs underlie cardio-metabolic derangements in obesity using a high fat, high sucrose (HFHS) diet in gpx4 haploinsufficient mice (GPx4(+/-)) and in samples of human myocardium.

Methods: Wild-type (WT) and GPx4(+/-) mice were fed either a standard chow (CNTL) or HFHS diet for 24 weeks, with metabolic and cardiovascular parameters measured throughout. Biochemical and immuno-histological analysis was performed in heart and liver at termination of study, and mitochondrial function was analyzed in heart. Biochemical analysis was also performed on samples of human atrial myocardium from a cohort of 103 patients undergoing elective heart surgery.

Results: Following HFHS diet, WT mice displayed moderate increases in 4-hydroxynonenal (HNE)-adducts and carbonyl stress, and a 1.5-fold increase in GPx4 enzyme in both liver and heart, while gpx4 haploinsufficient (GPx4(+/-)) mice had marked carbonyl stress in these organs accompanied by exacerbated glucose intolerance, dyslipidemia, and liver steatosis. Although normotensive, cardiac hypertrophy was evident with obesity, and cardiac fibrosis more pronounced in obese GPx4(+/-) mice. Mitochondrial dysfunction manifesting as decreased fat oxidation capacity and increased reactive oxygen species was also present in obese GPx4(+/-) but not WT hearts, along with up-regulation of pro-inflammatory and pro-fibrotic genes. Patients with diabetes and hyperglycemia exhibited significantly less GPx4 enzyme and greater HNE-adducts in their hearts, compared with age-matched non-diabetic patients.

Conclusion: These findings suggest LPPs are key factors underlying cardio-metabolic derangements that occur with obesity and that GPx4 serves a critical role as an adaptive countermeasure.

No MeSH data available.


Related in: MedlinePlus

Cardiac structural and functional parameters. Panels shown are representative images of whole hearts A, cardiac collagen stained with picosirius red under polarized light B,C, and Masson's Trichrome stained cardiac tissue D, from mice within each study group. Shown in E are heart weight/tibia length ratio, cardiomyocyte diameter F, and serum BNP levels G. Cardiac contractility H, mean arterial pressure I, and heart rate J are shown for each group Images are representative of 16 image fields captured per mouse, n = 2–3 mice per treatment group. Data in E-J are shown as mean ± S.E.M., n = 6–8 mice per group. *P < 0.05 vs. WT-CNTL, †P < 0.05 vs. WT-HFHS, §P < 0.05 vs. GPx4+/--CNTL.
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fig2: Cardiac structural and functional parameters. Panels shown are representative images of whole hearts A, cardiac collagen stained with picosirius red under polarized light B,C, and Masson's Trichrome stained cardiac tissue D, from mice within each study group. Shown in E are heart weight/tibia length ratio, cardiomyocyte diameter F, and serum BNP levels G. Cardiac contractility H, mean arterial pressure I, and heart rate J are shown for each group Images are representative of 16 image fields captured per mouse, n = 2–3 mice per treatment group. Data in E-J are shown as mean ± S.E.M., n = 6–8 mice per group. *P < 0.05 vs. WT-CNTL, †P < 0.05 vs. WT-HFHS, §P < 0.05 vs. GPx4+/--CNTL.

Mentions: Previous studies have shown that HFHS diet-induced obesity causes significant cardiac hypertrophy and left ventricular (LV) diastolic dysfunction in rodent models [46–48]. Here, HFHS diet caused an increase in cardiac mass to a similar extent between WT and GPx4+/− mice (Figure 2A,E). However, compared with WT, GPx4+/− mice display significantly greater cardiomyocyte diameter (Figure 2E,F) and fibrosis (Figure 2B,C) following HFHS diet. Obese mice also have increased levels of serum brain natriuretic peptide (BNP, Figure 2G), indicative of ventricular wall stress. This evidence of cardiomyopathy exists in the absence of any changes in LV systolic function (Figure 2H), blood pressure (Figure 2I) or heart rate (Figure 2J) in the mice following HFHS diet, indicating that any cardiomyopathy which might be present in these mice is not due to increased afterload.


Obesity in a model of gpx4 haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathy.

Katunga LA, Gudimella P, Efird JT, Abernathy S, Mattox TA, Beatty C, Darden TM, Thayne KA, Alwair H, Kypson AP, Virag JA, Anderson EJ - Mol Metab (2015)

Cardiac structural and functional parameters. Panels shown are representative images of whole hearts A, cardiac collagen stained with picosirius red under polarized light B,C, and Masson's Trichrome stained cardiac tissue D, from mice within each study group. Shown in E are heart weight/tibia length ratio, cardiomyocyte diameter F, and serum BNP levels G. Cardiac contractility H, mean arterial pressure I, and heart rate J are shown for each group Images are representative of 16 image fields captured per mouse, n = 2–3 mice per treatment group. Data in E-J are shown as mean ± S.E.M., n = 6–8 mice per group. *P < 0.05 vs. WT-CNTL, †P < 0.05 vs. WT-HFHS, §P < 0.05 vs. GPx4+/--CNTL.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4443294&req=5

fig2: Cardiac structural and functional parameters. Panels shown are representative images of whole hearts A, cardiac collagen stained with picosirius red under polarized light B,C, and Masson's Trichrome stained cardiac tissue D, from mice within each study group. Shown in E are heart weight/tibia length ratio, cardiomyocyte diameter F, and serum BNP levels G. Cardiac contractility H, mean arterial pressure I, and heart rate J are shown for each group Images are representative of 16 image fields captured per mouse, n = 2–3 mice per treatment group. Data in E-J are shown as mean ± S.E.M., n = 6–8 mice per group. *P < 0.05 vs. WT-CNTL, †P < 0.05 vs. WT-HFHS, §P < 0.05 vs. GPx4+/--CNTL.
Mentions: Previous studies have shown that HFHS diet-induced obesity causes significant cardiac hypertrophy and left ventricular (LV) diastolic dysfunction in rodent models [46–48]. Here, HFHS diet caused an increase in cardiac mass to a similar extent between WT and GPx4+/− mice (Figure 2A,E). However, compared with WT, GPx4+/− mice display significantly greater cardiomyocyte diameter (Figure 2E,F) and fibrosis (Figure 2B,C) following HFHS diet. Obese mice also have increased levels of serum brain natriuretic peptide (BNP, Figure 2G), indicative of ventricular wall stress. This evidence of cardiomyopathy exists in the absence of any changes in LV systolic function (Figure 2H), blood pressure (Figure 2I) or heart rate (Figure 2J) in the mice following HFHS diet, indicating that any cardiomyopathy which might be present in these mice is not due to increased afterload.

Bottom Line: Biochemical and immuno-histological analysis was performed in heart and liver at termination of study, and mitochondrial function was analyzed in heart.Mitochondrial dysfunction manifesting as decreased fat oxidation capacity and increased reactive oxygen species was also present in obese GPx4(+/-) but not WT hearts, along with up-regulation of pro-inflammatory and pro-fibrotic genes.Patients with diabetes and hyperglycemia exhibited significantly less GPx4 enzyme and greater HNE-adducts in their hearts, compared with age-matched non-diabetic patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology & Toxicology, East Carolina University, Greenville, NC, United States ; Department of Public Health, East Carolina University, Greenville, NC, United States.

ABSTRACT

Objective: Lipid peroxides and their reactive aldehyde derivatives (LPPs) have been linked to obesity-related pathologies, but whether they have a causal role has remained unclear. Glutathione peroxidase 4 (GPx4) is a selenoenzyme that selectively neutralizes lipid hydroperoxides, and human gpx4 gene variants have been associated with obesity and cardiovascular disease in epidemiological studies. This study tested the hypothesis that LPPs underlie cardio-metabolic derangements in obesity using a high fat, high sucrose (HFHS) diet in gpx4 haploinsufficient mice (GPx4(+/-)) and in samples of human myocardium.

Methods: Wild-type (WT) and GPx4(+/-) mice were fed either a standard chow (CNTL) or HFHS diet for 24 weeks, with metabolic and cardiovascular parameters measured throughout. Biochemical and immuno-histological analysis was performed in heart and liver at termination of study, and mitochondrial function was analyzed in heart. Biochemical analysis was also performed on samples of human atrial myocardium from a cohort of 103 patients undergoing elective heart surgery.

Results: Following HFHS diet, WT mice displayed moderate increases in 4-hydroxynonenal (HNE)-adducts and carbonyl stress, and a 1.5-fold increase in GPx4 enzyme in both liver and heart, while gpx4 haploinsufficient (GPx4(+/-)) mice had marked carbonyl stress in these organs accompanied by exacerbated glucose intolerance, dyslipidemia, and liver steatosis. Although normotensive, cardiac hypertrophy was evident with obesity, and cardiac fibrosis more pronounced in obese GPx4(+/-) mice. Mitochondrial dysfunction manifesting as decreased fat oxidation capacity and increased reactive oxygen species was also present in obese GPx4(+/-) but not WT hearts, along with up-regulation of pro-inflammatory and pro-fibrotic genes. Patients with diabetes and hyperglycemia exhibited significantly less GPx4 enzyme and greater HNE-adducts in their hearts, compared with age-matched non-diabetic patients.

Conclusion: These findings suggest LPPs are key factors underlying cardio-metabolic derangements that occur with obesity and that GPx4 serves a critical role as an adaptive countermeasure.

No MeSH data available.


Related in: MedlinePlus