Hypertriglyceridemia Results From an Impaired Catabolism of Triglyceride-Rich Lipoproteins in PLIN1-Related Lipodystrophy
Arteriosclerosis, Thrombosis, and Vascular Biology
Abstract
BACKGROUND:
Pathogenic variants in PLIN1-encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1-related FPL.
METHODS:
We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1-mutated FPL and 3 controls.
RESULTS:
Patients with PLIN1-mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P=0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P<0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P=0.006). Compared with controls, patients with PLIN1-related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P=0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P=0.005). VLDL-apoB100 production was not different between patients with PLIN1-related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1-related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (P=0.031) and IDL-apoB100 (P=0.031). Plasma LPL mass was significantly lower in patients with PLIN1-related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P<0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass.
CONCLUSIONS:
We show that hypertriglyceridemia associated with PLIN1-related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.
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© 2024 American Heart Association, Inc.
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History
Received: 25 January 2024
Accepted: 3 June 2024
Published online: 20 June 2024
Published in print: August 2024
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Sources of Funding
E. Capel and C. Vigouroux are supported by institutional fundings from the Institut National de la Santé et de la Recherche Médicale (Inserm), Sorbonne Université, Assistance-Publique Hôpitaux de Paris, Fondation pour la Recherche Médicale (grant number EQU201903007868), and the French Ministry of Health and of Higher Education and Research (Plan National Maladies Rares 3), the French National Research Agency (ANR: Agence nationale pour la Recherche) under the program “Investissements d’Avenir” with reference ANR-11-LABX-0021 (LipSTIC Labex). C. Vigouroux is a member of the European Reference Network on Rare Endocrine Conditions—project ID no. 739527.
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