Hypertriglyceridemia Results From an Impaired Catabolism of Triglyceride-Rich Lipoproteins in -Related Lipodystrophy.

BACKGROUND

Pathogenic variants in -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 -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. mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 -mutated FPL and 3 controls.

RESULTS

Patients with -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; =0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; <0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, =0.006). Compared with controls, patients with -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; =0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; =0.005). VLDL-apoB100 production was not different between patients with -related FPL and controls. Compared with patients with type 2 diabetes, patients with -related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (=0.031) and IDL-apoB100 (=0.031). Plasma LPL mass was significantly lower in patients with -related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; <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 -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.