Silencing the Very Low-density Lipoprotein Receptor (VLDLR) Prevents Obesity Associated with Excess Lipid Deposition (P21-040-19)
| Autor: | Tahar Hajri, Samuel A. Besong, Thomas V. Fungwe |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Apolipoprotein E
medicine.medical_specialty Nutrition and Dietetics Chemistry Leptin Glucose uptake Insulin medicine.medical_treatment Medicine (miscellaneous) Very Low-Density Lipoprotein Receptor Lipid metabolism medicine.disease Endocrinology Insulin resistance Internal medicine LDL receptor medicine Obesity Food Science |
| Popis: | OBJECTIVES: Obesity is associated with an insulin resistant state, characterized by abnormalities in lipid metabolism, a leading cause of morbidity and mortality in cardiovascular diseases (CVD). Very low-density lipoprotein receptor (VLDLR), a member of the LDL receptor family, binds and increases the catabolism of apolipoprotein E triglyceride-rich lipoproteins. Although VLDLR is highly expressed in the heart, its role in obesity associated lipotoxicity is not well understood. METHODS: In the current study, lean WT, VLDLR-deficient (VLDLR(−/−)), genetically obese leptin-deficient (Lep(ob/ob)), and leptin–VLDLR double-null (Lep(ob/ob)/VLDLR(−/−)) mice were used to determine the impact of VLDLR deficiency on obesity-induced cardiac lipotoxicity. RESULTS: The results showed that insulin sensitivity and glucose uptake were reduced in the hearts of Lep(ob/ob) mice, and at the same time, VLDLR expression was upregulated and associated with increased VLDL uptake resulting in excess lipid deposition. These changes were accompanied by upregulation of cardiac NADPH oxidase (Nox) expression and increased production of Nox-dependent superoxides. Silencing the VLDLR in Lep(ob/ob) mice reduced VLDL uptake and prevented excess lipid deposition. Moreover, VLDLR deficiency reduced superoxide overproduction and normalized glucose uptake. In isolated cardiomyocytes, VLDLR deficiency prevented VLDL-mediated induction of NOx activity and superoxide overproduction while improving insulin sensitivity and glucose uptake. An important observation showed that Lep(ob/ob)/VLDLR(−/−) mice compared to Lep(ob/ob) mice, had significantly improved heart performance and energetic reserves. CONCLUSIONS: These findings suggest that that when VLDLR is silenced (deficiency), lipid deposition is also reduced, preventing cardiac lipotoxicity in obesity. In addition, the effects may be linked to the role of VLDLR on VLDL uptake, which triggers a cascade of events leading to insulin resistance and superoxide overproduction. FUNDING SOURCES: Institutional Support. Howard University, Washington DC 20059 Hackensack University Medical Center, NJ 07601 |
| Databáze: | OpenAIRE |
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