SUN-087 Effects of Leptin Replacement on Circulating Plasma Inhibitors of Lipoprotein Lipase in Patients with Lipodystrophy

Abstract

Lipodystrophy syndromes (LD) result from selective deficiency of adipose tissue, leading to low leptin. Low leptin leads to hyperphagia and ectopic lipid storage, causing severe insulin resistance and metabolic complications including high triglycerides (TG) and subsequent pancreatitis. Replacement of leptin using metreleptin (ML) in LD decreases TG. TG are broken down to non-esterified fatty acids (NEFA) by lipoprotein lipase (LPL). We previously demonstrated that patients with LD had high apoCIII and ANGPLT8 (inhibitors of LPL) that decreased with ML, suggesting that ML may lower TG by reducing inhibition of LPL activity. We hypothesized that plasma from patients with LD would cause greater inhibition of LPL compared to controls, and that ML would ameliorate this. We further hypothesized that net inhibition of LPL in LD would be reflected by a decreased ratio of apoCII (an LPL stimulator) to apoCIII (an LPL inhibitor) vs. controls. METHODS: Plasma from ML-naive patients with LD (n=14) and a pooled high-TG control group (651 mg/dL, n=10) were diluted to the same concentration of TG. Samples were incubated with bovine LPL, and NEFA produced was measured enzymatically over 1hr at 37⁰C. Because the concentrations of added LPL and TG were equal in each patient sample, NEFA generation (nmole) reflected the net effect of LPL stimulators and inhibitors in plasma. To test the effects of ML, the same method was applied to samples from patients with LD after ML 5 mg Q12h for 2 weeks and 6 months. ApoCII and apoCIII were compared in patients with LD (n=14) versus healthy controls (TG = 74 [54, 97] mg/dL, n=28). RESULTS: Patients with LD had baseline TG 492 [208, 1016] mg/dL which decreased to 279 [171, 648] after 2 weeks of ML (n=14, p=.0023) and to 223 [118, 335] after 6 months of ML (n=11, p=0.15). Prior to ML, patients with LD had higher NEFA generation vs. controls (patients 0.79 ± 0.08; controls 0.59 ± 0.1; p<0.0001), consistent with less net inhibition of LPL. NEFA generation did not change with ML therapy after 2 weeks (0.77 ± 0.09) or 6 months (0.78 ± 0.12) compared to baseline (p>0.05). ApoCII:apoCIII ratio did not differ in LD vs controls (0.63±0.31 vs 0.54±0.17, p=0.6), and did not change after ML. CONCLUSIONS: Counter to our hypothesis, patients with LD had higher NEFA generation compared to high TG controls, consistent with less net inhibition of LPL, while the ratio of LPL activator (apoCII) to inhibitor (apoCIII) did not differ in LD vs normal TG controls. Furthermore, NEFA generation and apoCII:apoCIII ratio did not change after ML therapy, suggesting no net change in inhibition of LPL with ML. These findings suggest that changes in circulating activators and inhibitors of LPL are not a major mechanism by which ML lowers TG in LD. Studies including direct measurement of LPL activity after heparin stimulation are needed to further explore the role of LPL in regulating TG in LD.