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Impact of simvastatin on adipose tissue: pleiotropic effects in vivo.

ABSTRACT: Statins belong to a class of drugs well known for their ability to reduce circulating low-density lipoprotein cholesterol. In addition to cholesterol lowering, they also exhibit potential antiinflammatory and antioxidant properties, suggesting that tissues other than liver may be targeted by statins to exert their beneficial metabolic effects. Adipocytes have received very little attention as a potential target of these drugs, possibly because adipocytes are not a major source of biosynthetic cholesterol. Here, we examine the effects of simvastatin on the secretory pathway, inflammation, and cellular metabolism of adipocytes as well as on whole-body insulin sensitivity. We find that statins have a selective effect on the secretion of the insulin-sensitizing adipokine adiponectin by reducing circulating levels of the high-molecular-weight form of adiponectin specifically with a concomitant increase in intracellular adiponectin levels. However, these effects on adiponectin do not translate into changes in metabolism or whole-body insulin sensitivity, potentially due to additional antiinflammatory properties of statins. In addition, ob/ob mice treated with statins have reduced adiposity and an altered ultrastructure of the plasma membrane with respect to caveolar histology. Our data demonstrate that statins have major effects on the cellular physiology of the adipocyte on multiple levels.

SUBMITTER: Khan T

PROVIDER: S-EPMC2795715 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Impact of simvastatin on adipose tissue: pleiotropic effects in vivo.

Khan Tayeba T Hamilton Mark P MP Mundy Dorothy I DI Chua Streamson C SC Scherer Philipp E PE

Endocrinology 20091009 12

Statins belong to a class of drugs well known for their ability to reduce circulating low-density lipoprotein cholesterol. In addition to cholesterol lowering, they also exhibit potential antiinflammatory and antioxidant properties, suggesting that tissues other than liver may be targeted by statins to exert their beneficial metabolic effects. Adipocytes have received very little attention as a potential target of these drugs, possibly because adipocytes are not a major source of biosynthetic ch ...[more]

PMID: 19819942

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Project description:BackgroundRecognition of adipose-related signaling in surgery is increasing, although direct interrogation of human adipose has been sparse. Few scenarios rival uremia for health impact. We hypothesized that adipose from uremic patients holds a relatively higher adipose-derived hormone and proinflammatory adipokine signature; we simultaneously evaluated the impact of clinical parameters on adipose phenotype.Materials and methodsAdipose was harvested from surgical patients. Histology and protein analyses were completed for select mediators.ResultsIn the overall cohort of 71 patients, the mean age was 63.4 y; 46.4% of patients had diabetes mellitus, 49.2% had hyperlipidemia, and 53.5% had coronary artery disease. Compared with nonuremic patients, uremic patients had one-tenth of the levels of leptin (P < 0.001), one-third of the levels of adiponectin (P < 0.001), and threefold higher levels of resistin (P < 0.001). Females had sixfold higher levels of leptin, 1.5-fold higher levels of adiponectin, and twofold higher levels of tumor necrosis factor alpha but equivalent resistin. There were differences in mediators when stratified by age. In both the obese and nonobese strata, we observed a concordant pattern of association (magnitude or significance) of uremia and leptin, adiponectin, and resistin. No differentials in other mediators emerged on body mass index stratification. Multiple regression analysis for leptin, adiponectin, and resistin (with age, gender, and uremia as independent variables) showed uremia as the highest independent predictor of all the three mediators.ConclusionsAdvanced chronic kidney disease is associated with perturbations in adipose-derived hormones (leptin, adiponectin, and resistin). Adipose adiponectin and leptin (in contrast to reported plasma levels) were lower in uremic patients; there is an inverse correlation between adipose resistin and renal function. Compared with other clinical parameters including body mass index, uremia dominates overall in determining adipose phenotype, highlighting the complex biological interplay between uremia and adipose biology.

Project description:ContextLipophilic plasma glucocorticoids are thought to gain rapid access to intracellular compartments in adipose tissue. In other organs, transport can be regulated in a steroid- and tissue-specific manner. Moreover, 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) generates additional cortisol within adipose.AimThe aim was to measure the rate of exchange of cortisol between plasma and adipose for comparison with rates of intracellular cortisol generation by 11βHSD1.Participants and interventionsWith ethical approval, otherwise healthy females (n = 6) undergoing hysterectomy for benign indications were infused with tracer 9,11,12,12-[(2)H](4)cortisol (d4-cortisol). Adipose biopsies and peripheral venous samples were obtained during surgery after 3.9-5.5 h of infusion. Glucocorticoids were quantified using liquid chromatography tandem mass spectrometry.ResultsIn plasma, d4-cortisol concentrations and appearance rates of cortisol and d3-cortisol (reflecting 11βHSD1 activity) did not change during surgery. In both omental and sc adipose, cortisol concentrations were lower than in plasma, consistent with differences in corticosteroid binding globulin, and enrichment with d4-cortisol was low (sc, 7.2 ± 0.6%; omental, 7.4 ± 0.7%; vs. plasma, 15.5 ± 1.0%). The rate of accumulation of d4-cortisol in adipose depots was 0.5 ± 0.1 (sc) and 0.4 ± 0.1 (omental) nmol/kg · h, and the proportion of intraadipose cortisol replaced each hour only 10.7 ± 1.0 and 10.4 ± 0.7%, respectively. The contribution of 11βHSD1 to this turnover could not be quantified because very little substrate d3-cortisone accumulated in adipose during infusion.ConclusionsSlow turnover of the adipose glucocorticoid pool suggests that rapid acute fluctuations in circulating cortisol are not reflected in adipose, so that 11βHSD1 activity (previously estimated to generate 9 nmol cortisol/kg · h in sc adipose) may play a relatively important role in modulating activation of glucocorticoid receptors.

Dataset Information

Impact of simvastatin on adipose tissue: pleiotropic effects in vivo.

Publications

Impact of simvastatin on adipose tissue: pleiotropic effects in vivo.

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