BACKGROUND Statins have pleiotropic effects on lipid metabolism. The relationship between these effects and future cardiovascular events is unknown. We characterized the changes in lipids upon pravastatin treatment and defined the relationship with risk reduction for future cardiovascular events.METHODS Plasma lipids (n = 342) were measured in baseline and 1-year follow-up samples from a Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study subcohort (n = 4991). The associations of changes in lipids with treatment and cardiovascular outcomes were investigated using linear and Cox regression. The effect of treatment on future cardiovascular outcomes was examined by the relative risk reduction (RRR).RESULTS Pravastatin treatment was associated with changes in 206 lipids. Species containing arachidonic acid were positively associated while phosphatidylinositol species were negatively associated with pravastatin treatment. The RRR from pravastatin treatment for cardiovascular events decreased from 23.5% to 16.6% after adjustment for clinical risk factors and change in LDL-cholesterol (LDL-C) and to 3.0% after further adjustment for the change in the lipid ratio PI(36:2)/PC(38:4). Change in PI(36:2)/PC(38:4) mediated 58% of the treatment effect. Stratification of patients into quartiles of change in PI(36:2)/PC(38:4) indicated no benefit of pravastatin in the fourth quartile.CONCLUSION The change in PI(36:2)/PC(38:4) predicted benefit from pravastatin, independent of change in LDL-C, demonstrating its potential as a biomarker for monitoring the clinical benefit of statin treatment in secondary prevention.TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry identifier ACTRN12616000535471.FUNDING Bristol-Myers Squibb; NHMRC grants 211086, 358395, and 1029754; NHMRC program grant 1149987; NHMRC fellowship 108026; and the Operational Infrastructure Support Program of the Victorian government of Australia.
Kaushala S. Jayawardana, Piyushkumar A. Mundra, Corey Giles, Christopher K. Barlow, Paul J. Nestel, Elizabeth H. Barnes, Adrienne Kirby, Peter Thompson, David R. Sullivan, Zahir H. Alshehry, Natalie A. Mellett, Kevin Huynh, Malcolm J. McConville, Sophia Zoungas, Graham S. Hillis, John Chalmers, Mark Woodward, Ian C. Marschner, Gerard Wong, Bronwyn A. Kingwell, John Simes, Andrew M. Tonkin, Peter J. Meikle, on behalf of the LIPID Study Investigators
Obesity-related insulin resistance is associated with intramyocellular lipid accumulation in skeletal muscle. We hypothesized that in contrast to current dogma, this linkage is related to an upstream mechanism that coordinately regulates both processes. We demonstrate that the muscle-enriched transcription factor MondoA is glucose/fructose responsive in human skeletal myotubes and directs the transcription of genes in cellular metabolic pathways involved in diversion of energy substrate from a catabolic fate into nutrient storage pathways including fatty acid desaturation and elongation, triacylglyeride (TAG) biosynthesis, glycogen storage, and hexosamine biosynthesis. MondoA also reduces myocyte glucose uptake by suppressing insulin signaling. Mice with muscle-specific MondoA deficiency were partially protected from insulin resistance and muscle TAG accumulation in the context of diet-induced obesity. These results identify MondoA as a nutrient-regulated transcription factor that under normal physiological conditions serves a dynamic checkpoint function to prevent excess energy substrate flux into muscle catabolic pathways when myocyte nutrient balance is positive. However, in conditions of chronic caloric excess, this mechanism becomes persistently activated leading to progressive myocyte lipid storage and insulin resistance.
Byungyong Ahn, Shibiao Wan, Natasha Jaiswal, Rick B. Vega, Donald E. Ayer, Paul M. Titchenell, Xianlin Han, Kyoung Jae Won, Daniel P. Kelly
Bile acids play a major role in the regulation of lipid and energy metabolism. Here we propose the hepatic bile acid uptake transporter Na+ taurocholate co-transporting polypeptide (NTCP) as a target to prolong postprandial bile acid elevations in plasma. Reducing hepatic clearance of bile acids from plasma by genetic deletion of NTCP moderately increased plasma bile acid levels, reduced diet-induced obesity, attenuated hepatic steatosis, and lowered plasma cholesterol levels. NTCP-G protein-coupled bile acid receptor (TGR5) double knockout mice were equally protected against diet-induced-obesity as NTCP single knockout mice. NTCP knockout mice displayed decreased intestinal fat absorption and a trend towards higher fecal energy output. Furthermore, NTCP deficiency was associated with an increased uncoupled respiration in brown adipose tissue, leading to increased energy expenditure. We conclude that targeting NTCP-mediated bile acid uptake can be a novel approach to treat obesity and obesity-related hepatosteatosis by simultaneously dampening intestinal fat absorption and increasing energy expenditure.
Joanne M. Donkers, Sander Kooijman, Davor Slijepcevic, Roni F. Kunst, Reinout L.P. Roscam Abbing, Lizette C.J.M Haazen, Dirk R. de Waart, Johannes H.M. Levels, Kristina Schoonjans, Patrick C.N. Rensen, Ronald P.J. Oude Elferink, Stan F.J. Van de Graaf
The increased formation of methylglyoxal (MG) under hyperglycemia is associated with the development of microvascular complications in patients with diabetes mellitus; however, the effects of elevated MG levels in vivo are poorly understood. In zebrafish, a transient knockdown of glyoxalase 1, the main MG detoxifying system, led to the elevation of endogenous MG levels and blood vessel alterations. To evaluate effects of a permanent knockout of glyoxalase 1 in vivo, glo1–/– zebrafish mutants were generated using CRISPR/Cas9. In addition, a diet-induced–obesity zebrafish model was used to analyze glo1–/– zebrafish under high nutrient intake. Glo1–/– zebrafish survived until adulthood without growth deficit and showed increased tissue MG concentrations. Impaired glucose tolerance developed in adult glo1–/– zebrafish and was indicated by increased postprandial blood glucose levels and postprandial S6 kinase activation. Challenged by an overfeeding period, fasting blood glucose levels in glo1–/– zebrafish were increased which translated into retinal blood vessel alterations. Thus, the data have identified a defective MG detoxification as a metabolic prerequisite and glyoxalase 1 alterations as a genetic susceptibility to the development of type 2 diabetes mellitus under high nutrition intake.
Elisabeth Lodd, Lucas M. Wiggenhauser, Jakob Morgenstern, Thomas H. Fleming, Gernot Poschet, Michael Büttner, Christoph T. Tabler, David P. Wohlfart, Peter P. Nawroth, Jens Kroll
BACKGROUND Metabolic syndrome (MetS) is highly correlated with obesity and cardiovascular risk, but the importance of dietary carbohydrate independent of weight loss in MetS treatment remains controversial. Here, we test the theory that dietary carbohydrate intolerance (i.e., the inability to process carbohydrate in a healthy manner) rather than obesity per se is a fundamental feature of MetS.METHODS Individuals who were obese with a diagnosis of MetS were fed three 4-week weight-maintenance diets that were low, moderate, and high in carbohydrate. Protein was constant and fat was exchanged isocalorically for carbohydrate across all diets.RESULTS Despite maintaining body mass, low-carbohydrate (LC) intake enhanced fat oxidation and was more effective in reversing MetS, especially high triglycerides, low HDL-C, and the small LDL subclass phenotype. Carbohydrate restriction also improved abnormal fatty acid composition, an emerging MetS feature. Despite containing 2.5 times more saturated fat than the high-carbohydrate diet, an LC diet decreased plasma total saturated fat and palmitoleate and increased arachidonate.CONCLUSION Consistent with the perspective that MetS is a pathologic state that manifests as dietary carbohydrate intolerance, these results show that compared with eucaloric high-carbohydrate intake, LC/high-fat diets benefit MetS independent of whole-body or fat mass.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02918422.FUNDING Dairy Management Inc. and the Dutch Dairy Association.
Parker N. Hyde, Teryn N. Sapper, Christopher D. Crabtree, Richard A. LaFountain, Madison L. Bowling, Alex Buga, Brandon Fell, Fionn T. McSwiney, Ryan M. Dickerson, Vincent J. Miller, Debbie Scandling, Orlando P. Simonetti, Stephen D. Phinney, William J. Kraemer, Sarah A. King, Ronald M. Krauss, Jeff S. Volek
Mutations in BSCL2 gene underlie human type 2 Berardinelli-Seip Congenital Lipodystrophy (BSCL2) disease. Global Bscl2−/− mice recapitulate human BSCL2 lipodystrophy and develop insulin resistance and hypertrophic cardiomyopathy. The pathological mechanisms underlying the development of lipodystrophy and cardiomyopathy in BSCL2 are controversial. Here we report that Bscl2−/− mice develop cardiac hypertrophy due to increased basal IGF1 receptor (IGF1R)-mediated PI3K/AKT signaling. Bscl2−/− hearts exhibited increased adipose triglyceride lipase (ATGL) protein stability and expression causing drastic reduction of glycerolipids. Excessive fatty acid oxidation was overt in Bscl2−/− hearts, partially attributing to the hyperacetylation of cardiac mitochondrial proteins. Intriguingly, pharmacological inhibition or genetic inactivation of ATGL could rescue adipocyte differentiation and lipodystrophy in Bscl2−/− cells and mice. Restoring a small portion of fat mass by ATGL partial deletion in Bscl2−/− mice not only reversed the systemic insulin resistance, but also ameliorated cardiac protein hyperacetylation, normalized cardiac substrate metabolism and improved contractile function. Collectively, our study uncovers novel pathways underlying lipodystrophy-induced cardiac hypertrophy and metabolic remodeling and pinpoints ATGL as a downstream target of BSCL2 in regulating the development of lipodystrophy and its associated cardiomyopathy.
Hongyi Zhou, Xinnuo Lei, Yun Yan, Todd Lydic, Jie Li, Neal L. Weintraub, Huabo Su, Weiqin Chen
The evolutionary conserved Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is one of the crucial multiprotein complexes that facilitates endosomal recycling of transmembrane proteins. Defects in WASH components have been associated with inherited developmental and neurological disorders in humans. Here, we show that hepatic ablation of the WASH component Washc1 in chow-fed mice increases plasma concentrations of cholesterol in both LDLs and HDLs, without affecting hepatic cholesterol content, hepatic cholesterol synthesis, biliary cholesterol excretion, or hepatic bile acid metabolism. Elevated plasma LDL cholesterol was related to reduced hepatocytic surface levels of the LDL receptor (LDLR) and the LDLR-related protein LRP1. Hepatic WASH ablation also reduced the surface levels of scavenger receptor class B type I and, concomitantly, selective uptake of HDL cholesterol into the liver. Furthermore, we found that WASHC1 deficiency increases LDLR proteolysis by the inducible degrader of LDLR, but does not affect proprotein convertase subtilisin/kexin type 9–mediated LDLR degradation. Remarkably, however, loss of hepatic WASHC1 may sensitize LDLR for proprotein convertase subtilisin/kexin type 9–induced degradation. Altogether, these findings identify the WASH complex as a regulator of LDL as well as HDL metabolism and provide in vivo evidence for endosomal trafficking of scavenger receptor class B type I in hepatocytes.
Melinde Wijers, Paolo Zanoni, Nalan Liv, Dyonne Y. Vos, Michelle Y. Jäckstein, Marieke Smit, Sanne Wilbrink, Justina C. Wolters, Ydwine T. van der Veen, Nicolette Huijkman, Daphne Dekker, Niels Kloosterhuis, Theo H. van Dijk, Daniel D. Billadeau, Folkert Kuipers, Judith Klumperman, Arnold von Eckardstein, Jan Albert Kuivenhoven, Bart van de Sluis
BACKGROUND. Dietary changes have led to a growing prevalence of Type 2 diabetes and non-alcoholic fatty liver disease. A hallmark of both disorders is hepatic lipid accumulation, derived in part from increased de novo lipogenesis. Despite high protein diets being popular for weight loss to tackle these metabolic disorders, the effect of dietary protein on de novo lipogenesis is poorly studied. We aimed to characterise the effect of dietary protein on de novo lipid synthesis. METHODS. Herein, we use a 3-way crossover interventional study in healthy males to determine the effect of high protein feeding on de novo lipogenesis as well as in vitro models to determine the effects of specific amino acids on fatty acid synthesis. The primary outcome was change in de novo lipogenesis-associated triglycerides in response to protein feeding. RESULTS. We demonstrate that high protein feeding, rich in glutamate, increases de novo lipogenesis-associated triglycerides in plasma (2-fold compared to Control; p < 0.0001) and liver-derived very low-density lipoprotein particles (1.8 fold; p < 0.0001) in samples from human subjects (n = 9 per group). In hepatocytes, we show that glutamate derived carbon is incorporated into palmitate and subsequently into triglycerides. In addition, supplementation with glutamate, glutamine and leucine, but not lysine increases synthesised triglyceride content in cells and decreases glucose uptake. Glutamate, glutamine and leucine increase activation of protein kinase B, suggesting that these amino acids induce de novo lipogenesis via the insulin signalling cascade. CONCLUSION. These findings provide mechanistic insight into how select amino acids may induce de novo lipogenesis and insulin resistance, suggesting that high protein feeding to tackle diabetes and obesity requires greater consideration.
Evelina Charidemou, Tom Ashmore, Xuefei Li, Ben D. McNally, James A. West, Sonia Liggi, Matthew Harvey, Elise Orford, Julian L. Griffin
The Mitochondrial Pyruvate Carrier (MPC) occupies a central metabolic node by transporting cytosolic pyruvate into the mitochondrial matrix and linking glycolysis with mitochondrial metabolism. Two reported human MPC1 mutations cause developmental abnormalities, neurological problems, metabolic deficits, and for one patient, early death. We aimed to understand biochemical mechanisms by which the human patient C289T and T236A MPC1 alleles disrupt MPC function. MPC1 C289T encodes two protein variants, a mis-spliced, truncation mutant (A58G) and a full length point mutant (R97W). MPC1 T236A encodes a full length point mutant (L79H). Using human patient fibroblasts and complementation of CRISPR-deleted, MPC1 null mouse C2C12 cells, we investigated how MPC1 mutations cause MPC deficiency. Truncated MPC1 A58G protein was intrinsically unstable and failed to form MPC complexes. The MPC1 R97W protein was less stable but when overexpressed formed complexes with MPC2 that retained pyruvate transport activity. Conversely, MPC1 L79H protein formed stable complexes with MPC2, but these complexes failed to transport pyruvate. These findings inform MPC structure-function relationships and delineate three distinct biochemical pathologies resulting from two human patient MPC1 mutations. They also illustrate an efficient gene pass-through system for mechanistically investigating human inborn errors in pyruvate metabolism.
Lalita Oonthonpan, Adam J. Rauckhorst, Lawrence R. Gray, Audrey C. Boutron, Eric B. Taylor
Diabetic β cell failure is associated with β cell dedifferentiation. To identify effector genes of dedifferentiation, we integrated analyses of histone methylation as a surrogate of gene activation status and RNA expression in β cells sorted from mice with multiparity-induced diabetes. Interestingly, only a narrow subset of genes demonstrated concordant changes to histone methylation and RNA levels in dedifferentiating β cells. Notable among them was the α cell signature gene Gc, encoding a vitamin D-binding protein. While diabetes was associated with Gc induction, Gc-deficient islets did not induce β cell dedifferentiation markers and maintained normal ex vivo insulin secretion in the face of metabolic challenge. Moreover, Gc-deficient mice exhibited a more robust insulin secretory response than normal controls during hyperglycemic clamps. The data are consistent with a functional role of Gc activation in β cell dysfunction, and indicate that multiparity-induced diabetes is associated with altered β cell fate.
Taiyi Kuo, Manashree Damle, Bryan J. González, Dietrich Egli, Mitchell A. Lazar, Domenico Accili
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