Farnesyl pyrophosphate regulates adipocyte functions as an endogenous PPARγ agonist

The cholesterol biosynthetic pathway produces not only sterols but also non-sterol mevalonate metabolites involved in isoprenoid synthesis. Mevalonate metabolites affect transcriptional and post-transcriptional events that in turn affect various biological processes including energy metabolism. In the present study, we examine whether mevalonate metabolites activate PPARγ (peroxisome-proliferator-activated receptor γ), a ligand-dependent transcription factor playing a central role in adipocyte differentiation. In the luciferase reporter assay using both GAL4 chimaera and full-length PPARγ systems, a mevalonate metabolite, FPP (farnesyl pyrophosphate), which is the precursor of almost all isoprenoids and is positioned at branch points leading to the synthesis of other longer-chain isoprenoids, activated PPARγ in a dose-dependent manner. FPP induced the in vitro binding of a co-activator, SRC-1 (steroid receptor co-activator-1), to GST (glutathione transferase)–PPARγ. Direct binding of FPP to PPARγ was also indicated by docking simulation studies. Moreover, the addition of FPP up-regulated the mRNA expression levels of PPARγ target genes during adipocyte differentiation induction. In the presence of lovastatin, an HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitor, both intracellular FPP levels and PPARγ-target gene expressions were decreased. In contrast, the increase in intracellular FPP level after the addition of zaragozic acid, a squalene synthase inhibitor, induced PPARγ-target gene expression. The addition of FPP and zaragozic acid promotes lipid accumulation during adipocyte differentiation. These findings indicated that FPP might function as an endogenous PPARγ agonist and regulate gene expression in adipocytes

Atorvastatin in factorial with omega-3 EE90 risk reduction in diabetes (AFORRD): A randomised controlled trial

AIMS/HYPOTHESIS: The aim of the study was to examine the impact of statin or omega-3-acid ethyl esters 90 (omega-3 EE90; omega-3-acid ethyl esters 90 refers to a mixture of ethyl esters of n-3 fatty acids) on estimated cardiovascular disease (CVD) risk in community-based people with type 2 diabetes but without known CVD and not taking lipid-lowering therapy. METHODS: A central computer randomised 800 patients in 59 UK general practices to atorvastatin (n = 401, 20 mg/day) or placebo (n = 399) and omega-3 EE90 (n = 397, 2 g/day) or placebo (n = 403) in a concealed factorial manner. Participants with LDL-cholesterol or=20%. Of 732 patients with 4-month data, more allocated atorvastatin (n = 371) compared with placebo (n = 361) achieved LDL-cholesterol <2.6 mmol/l (91% vs 24%, p < 0.001) and had estimated 10-year CVD risks <20% (38% vs 26%, p < 0.001). No differences were seen between those allocated omega-3 EE90 (n = 371) compared with placebo (n = 361) for participants achieving triacylglycerol <1.5 mmol/l (65% vs 60%, p = 0.18) or estimated 10-year CVD risks <20% (34% vs 30%, p = 0.18). There were no side effects of note. CONCLUSIONS/INTERPRETATION: Many community-based diabetic patients without known CVD remain at high CVD risk despite statin treatment and require additional risk-reduction strategies. The impact of omega-3 EE90 on CVD risk will remain uncertain until clinical endpoint trial results are available. TRIAL REGISTRATION: ISRCT no. 76737502

Statin therapy and plasma free fatty acids: a systematic review and meta-analysis of controlled clinical trials

AIM: The aim of this meta‐analysis was to evaluate the effect of statin therapy on plasma FFA concentrations in a systematic review and meta‐analysis of controlled clinical trials. METHODS: PubMed‐Medline, SCOPUS, Web of Science and Google Scholar databases were searched (from inception to February 16 2015) to identify controlled trials evaluating the impact of statins on plasma FFA concentrations. A systematic assessment of bias in the included studies was performed using the Cochrane criteria. A random effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave‐one‐out method. Random effects meta‐regression was performed using unrestricted maximum likelihood method to evaluate the impact of potential moderators. RESULTS: Meta‐analysis of data from 14 treatment arms indicated a significant reduction in plasma FFA concentrations following treatment with statins (weighted mean difference (WMD) –19.42%, 95% CI –23.19, −–15.64, P < 0.001). Subgroup analysis confirmed the significance of the effect with both atorvastatin (WMD –20.56%, 95% CI –24.51, –16.61, P < 0.01) and simvastatin (WMD –18.05%, 95% CI –28.12, –7.99, P < 0.001). Changes in plasma FFA concentrations were independent of treatment duration (slope –0.10, 95% CI –0.30, 0.11, P = 0.354) and magnitude of reduction in plasma low density lipoprotein cholesterol concentrations (slope 0.55, 95% CI –0.17, 1.27, P = 0.133) by statins. CONCLUSIONS: The results of the present study suggest that statin therapy may lower plasma FFA concentrations. The cardiovascular and metabolic significance of this finding requires further investigation