H igh-density lipoprotein (HDL)-based therapies have yielded disappointing results, [1][2][3][4] which have led to questioning of the HDL hypothesis. Cholesteryl ester transfer protein mediates the transfer of cholesteryl esters from HDL to apolipoprotein B-containing particles, such as low-density lipoproteins (LDLs).5 Torcetrapib, the first cholesteryl ester transfer protein inhibitor to be evaluated in a large clinical trial, caused excess morbidity and mortality despite increasing HDL-cholesterol levels by ≈70% although elevations of aldosterone levels and blood pressure observed in some patients may have contributed to the negative findings.3 Dalcetrapib is another cholesteryl ester transfer protein inhibitor that raises HDL-cholesterol levels by ≈30%, without effects on circulating neurohormones. 6 The dal-OUTCOMES trial was designed to test whether dalcetrapib could modify cardiovascular risk in patients with a recent acute coronary syndrome. Background-Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein as a therapeutic target. Responses to dalcetrapib may vary according to patients' genetic profile. Methods and Results-We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10 -8 ), with 8 polymorphisms providing P<10 -6 in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41-0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten single-nucleotide polymorphism in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (P<0.05). Marker rs2238448 in ADCY9, in linkage disequilibrium with rs1967309 (r 2 =0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88×10 -8 ; hazard ratio, 0.67; 95% confidence interval, 0.58-0.78). Conclusions-The Tardif et al Pharmacogenomic Determinants of Dalcetrapib 373Dalcetrapib failed to improve clinical outcomes among the 15 871 patients of the dal-OUTCOMES study, with no subgroups defined by baseline clinical or biochemical characteristics appearing to benefit from therapy. 4 These results are ...

We examined in HepG2 cells whether glucose-induced changes in AMP-activated protein kinase (AMPK) activity could be mediated by SIRT1, an NAD-dependent histone/protein deacetylase that has been linked to the increase in longevity caused by caloric restriction. Incubation with 25 vs. 5 mM glucose for 6 h concurrently diminished the phosphorylation of AMPK (Thr 172) and ACC (Ser 79), increased lactate release, and decreased the abundance and activity of SIRT1. In contrast, incubation with pyruvate (0.1 and 1 mM) for 2 h increased AMPK phosphorylation and SIRT1 abundance and activity. The putative SIRT1 activators resveratrol and quercetin also increased AMPK phosphorylation. None of the tested compounds (low or high glucose, pyruvate, and resveratrol) significantly altered the AMP/ATP ratio. Collectively, these findings raise the possibility that glucose-induced changes in AMPK are linked to alterations in SIRT1 abundance and activity and possibly cellular redox state.

Assifi, Murwarid M., Gabriela Suchankova, Scarlet Constant, Marc Prentki, Asish K. Saha, and Neil B. Ruderman. AMP-activated protein kinase and coordination of hepatic fatty acid metabolism of starved/carbohydrate-refed rats. Am J Physiol Endocrinol Metab 289: E794-E800, 2005. First published June 14, 2005; doi:10.1152/ajpendo.00144.2005.-Acute increases in the concentration of malonyl-CoA play a pivotal role in mediating the decrease in fatty acid oxidation that occurs in many tissues during refeeding after a fast. In this study, we assess whether such increases in malonyl-CoA in liver could be mediated by malonyl-CoA decarboxylase (MCD), as well as acetyl-CoA carboxylase (ACC). In addition, we examine how changes in the activity of ACC, MCD, and other enzymes that govern fatty acid and glycerolipid synthesis relate temporally to alterations in the activities of the fuel-sensing enzyme AMP-activated protein kinase (AMPK). Rats starved for 48 h and refed a carbohydrate chow diet for 1, 3, 12, and 24 h were studied. Refeeding caused a 40% decrease in the activity of the ␣1-isoform of AMPK within 1 h, with additional decreases in AMPK␣1 activity and a decrease in AMPK␣2 occurring between 1 and 24 h. At 1 h, the decrease in AMPK activity was associated with an eightfold increase in the activity of the ␣1-isoform of ACC and a 30% decrease in the activity of MCD, two enzymes thought to be regulated by AMPK. Also, the concentration of malonyl-CoA was increased by 50%. Between 1 and 3 h of refeeding, additional increases in the activity of ACC and decreases in MCD were observed, as was a further twofold increase in malonyl-CoA. Increases in the activity (60%) and abundance (12-fold) of fatty acid synthase occurred predominantly between 3 and 24 h and increases in the activity of mitochondrial sn-glycerol-3-phosphate acyltransferase (GPAT) and acyl-CoA:diaclyglycerol acyltransferase (DGAT) at 12 and 24 h. The results strongly suggest that early changes in the activity of MCD, as well as ACC, contribute to the increase in hepatic malonyl-CoA in the starved-refed rat. They also suggest that the changes in these enzymes, and later occurring increases in enzymes regulating fatty acid and glycerolipid synthesis, could be coordinated by AMPK.acetyl-coenzyme A carboxylase; acyl-coenzyme A:diaclyglycerol acyltransferase; glycerol phosphate acyltransferase; malonyl-coenzyme A; malonyl-coenzyme A decarboxylase THE TRANSITION FROM THE FASTED TO THE FED STATE is associated with nutritional and hormonal changes that lead to increased hepatic glycerolipid and fatty acid synthesis and decreased fatty acid oxidation and ketogenesis (41). Many of the enzymes that mediate these events have been identified, as have the hormonal factors and molecular mechanism(s) by which their activity is altered (2,8,16,17,28, 45,53). We examine here the possibility that the changes in activity of these enzymes during refeeding are coordinated by AMP-activated protein kinase (AMPK). AMPK belongs to a family of highly conserved serine kinases that are reg...

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