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Nuclear receptors regulate lipid metabolism and oxidative stress markers in chondrocytes.

ABSTRACT: Joint homeostasis failure can result in osteoarthritis (OA). Currently, there are no treatments to alter disease progression in OA, but targeting early changes in cellular behavior has great potential. Recent data show that nuclear receptors contribute to the pathogenesis of OA and could be viable therapeutic targets, but their molecular mechanisms in cartilage are incompletely understood. This study examines global changes in gene expression after treatment with agonists for four nuclear receptor implicated in OA (LXR, PPAR?, PPAR?, and RXR). Murine articular chondrocytes were treated with agonists for LXR, PPAR?, PPAR?, or RXR and underwent microarray, qPCR, and cellular lipid analyses to evaluate changes in gene expression and lipid profile. Immunohistochemistry was conducted to compare two differentially expressed targets (Txnip, Gsta4) in control and cartilage-specific PPAR? knockout mice subjected to surgical destabilization of the medial meniscus (DMM). Nuclear receptor agonists induced different gene expression profiles with many responses affecting lipid metabolism. LXR activation downregulated gene expression of proteases involved in OA, whereas RXR agonism decreased expression of ECM components and increased expression of Mmp13. Functional assays indicate increases in cell triglyceride accumulation after PPAR?, LXR, and RXR agonism but a decrease after PPAR? agonism. PPAR? and RXR downregulate the antioxidant Gsta4, and PPAR? upregulates Txnip. Wild-type, but not PPAR?-deficient mice, display increased staining for Txnip after DMM. Collectively, these data demonstrate that nuclear receptor activation in chondrocytes primarily affects lipid metabolism. In the case of PPAR?, this change might lead to increased oxidative stress, possibly contributing to OA-associated changes.

Key message

Nuclear receptors regulate metabolic genes in chondrocytes. Nuclear receptors affect triglyceride levels. PPAR? mediates regulation of oxidative stress markers. Nuclear receptors are promising therapeutic targets for osteoarthritis.

SUBMITTER: Ratneswaran A

PROVIDER: S-EPMC5357281 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Nuclear receptors regulate lipid metabolism and oxidative stress markers in chondrocytes.

Ratneswaran Anusha A Sun Margaret Man-Ger MM Dupuis Holly H Sawyez Cynthia C Borradaile Nica N Beier Frank F

Journal of molecular medicine (Berlin, Germany) 20170109 4

Joint homeostasis failure can result in osteoarthritis (OA). Currently, there are no treatments to alter disease progression in OA, but targeting early changes in cellular behavior has great potential. Recent data show that nuclear receptors contribute to the pathogenesis of OA and could be viable therapeutic targets, but their molecular mechanisms in cartilage are incompletely understood. This study examines global changes in gene expression after treatment with agonists for four nuclear recept ...[more]

PMID: 28070626

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Project description:In lung cancer (LC), alterations in redox balance are extensively observed and are a consequence of disease as well as co-occurrent with smoking. We previously demonstrated that metabolic disturbances such as trace element status and carbohydrate metabolism alterations are linked with redox status. The aim of this study was to evaluate relationships between the serum parameters of lipid metabolism and redox balance in LC patients. Serum parameters of lipid metabolism, i.e. total cholesterol (T-C), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TG), T-C:HDL-C ratio, non-HDL-C, apolipoprotein A1 (Apo-A1), apolipoprotein B (Apo-B) and Apo-B:Apo-A1 ratio, as well as systemic redox status, i.e. total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), vitamin E (VE), vitamin C (VC), malonyldialdehyde (MDA), conjugated dienes (CD), and 4-hydroxynonenal (4-HNE) were determined in 92 LC patients and 82 control subjects (CS). LC women had significantly lower T-C and LDL-C, and higher TG, while HDL-C, Apo-A1 and Apo-B were significantly decreased in LC patients regardless of sex, when compared to CS. LC men had alterations in the systemic total redox balance such as lower TAS and higher OSI than CS men. LC women had lower VC, but VE was decreased in LC patients, regardless of sex. We observed higher lipid peroxidation in LC patients expressed via higher 4-HNE and CD. Systemic redox disturbances were associated with serum lipid alterations: TOS and OSI were positively correlated with T-C:HDL-C ratio and Apo-B:Apo-A1 ratio and negatively with HDL-C. The parameters of lipid peroxidation CD and MDA were significantly associated with variables reflecting lipid disturbances. The observed correlations were strengthened by general overweight/obesity, abdominal obesity, hypertriglyceridemia and non-smoking status. In conclusion, parameters related to lipid alterations are associated with oxidative stress in LC patients. The largest contribution from lipid parameters was revealed for T-C:HDL-C ratio, HDL-C and Apo-B:Apo-A1 ratio, while the largest contribution from redox status was revealed for OSI and VE. Overweight, obesity, hypertriglyceridemia and non-smoking status intensified these relationships.

Dataset Information

Nuclear receptors regulate lipid metabolism and oxidative stress markers in chondrocytes.

Key message

Publications

Nuclear receptors regulate lipid metabolism and oxidative stress markers in chondrocytes.

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