Human PAH is characterized by a pattern of lipid-related insulin resistance.

Autor:	Hemnes AR; Division of Allergy, Pulmonary and Critical Care Medicine and., Luther JM; Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Rhodes CJ; Centre for Pharmacology and Therapeutics, Department of Medicine, Hammersmith Campus, Imperial College, London, United Kingdom., Burgess JP; Leco Corporation, St. Joseph, Michigan, USA., Carlson J; RTI International, Research Triangle Park, North Carolina, USA., Fan R; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Fessel JP; Division of Allergy, Pulmonary and Critical Care Medicine and., Fortune N; Division of Allergy, Pulmonary and Critical Care Medicine and., Gerszten RE; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA., Halliday SJ; Division of Allergy, Pulmonary and Critical Care Medicine and., Hekmat R; Cardiovascular Medicine Division, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Howard L; National Heart and Lung Institute, Imperial College, London and National Pulmonary Hypertension Service, Hammersmith Hospital, London, United Kingdom., Newman JH; Division of Allergy, Pulmonary and Critical Care Medicine and., Niswender KD; Division of Diabetes, Endocrinology, and Metabolism and., Pugh ME; Division of Allergy, Pulmonary and Critical Care Medicine and., Robbins IM; Division of Allergy, Pulmonary and Critical Care Medicine and., Sheng Q; Division of Cancer Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Shibao CA; Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Shyr Y; Division of Cancer Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Sumner S; NIH Common Fund Eastern Regional Comprehensive Metabolomics Resource Core, School of Public Health, University of North Carolina at Chapel Hill, Kannapolis, North Carolina, USA., Talati M; Division of Allergy, Pulmonary and Critical Care Medicine and., Wharton J; Centre for Pharmacology and Therapeutics, Department of Medicine, Hammersmith Campus, Imperial College, London, United Kingdom., Wilkins MR; Centre for Pharmacology and Therapeutics, Department of Medicine, Hammersmith Campus, Imperial College, London, United Kingdom., Ye F; Division of Cancer Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Yu C; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA., West J; Division of Allergy, Pulmonary and Critical Care Medicine and., Brittain EL; Cardiovascular Medicine Division, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2019 Jan 10; Vol. 4 (1). Date of Electronic Publication: 2019 Jan 10.
DOI:	10.1172/jci.insight.123611
Abstrakt:	Background: Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose- and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH. Methods: Oral glucose tolerance testing in PAH patients and triglyceride-matched (TG-matched) controls and proteomic, metabolomics, and lipoprotein analyses were performed in PAH and controls. Results were validated in an external cohort and in explanted human PAH lungs. Results: PAH patients were similarly glucose intolerant or IR by glucose homeostasis metrics compared with control patients when matched for the metabolic syndrome. Using the insulin-sensitive lipoprotein index, TG/HDL ratio, PAH patients were more commonly IR than controls. Proteomic and metabolomic analysis demonstrated separation between PAH and controls, driven by differences in lipid species. We observed a significant increase in long-chain acylcarnitines, phosphatidylcholines, insulin metabolism-related proteins, and in oxidized LDL receptor 1 (OLR1) in PAH plasma in both a discovery and validation cohort. PAH patients had higher lipoprotein axis-related IR and lipoprotein-based inflammation scores compared with controls. PAH patient lung tissue showed enhanced OLR1 immunostaining within plexiform lesions and oxidized LDL accumulation within macrophages. Conclusions: IR in PAH is characterized by alterations in lipid and lipoprotein homeostasis axes, manifest by elevated TG/HDL ratio, and elevated circulating medium- and long-chain acylcarnitines and lipoproteins. Oxidized LDL and its receptor OLR1 may play a role in a proinflammatory phenotype in PAH. Funding: NIH DK096994, HL060906, UL1 RR024975-01, UL1 TR000445-06, DK020593, P01 HL108800-01A1, and UL1 TR002243; American Heart Association 13FTF16070002.
Databáze:	MEDLINE
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