RF04 | PSUN333 Divergent Pathways in Liver Triglyceride Storage and Secretion in Partial Lipodystrophy vs. Obesity Associated NAFLD

Abstract

Abstract Background Partial lipodystrophy (PL) syndromes are characterized by deficiency of subcutaneous fat, increased liver fat and insulin resistance (IR). Nonalcoholic fatty liver disease (NAFLD) is an important cause of morbidity and mortality in both PL and obesity. Hepatic lipid derives from re-esterification of free fatty acids (FFA) from adipose tissue lipolysis and dietary sources, as well as de novo lipogenesis. Hepatic TG can be used for energy by β-oxidation, stored in hepatocytes as lipid droplets or secreted as VLDL. Hepatosteatosis develops when the rate of intrahepatic TG production is greater than the rate of TG disposal (oxidation and secretion). Here we investigate the contributions of insulin resistance and adipose tissue to hepatic steatosis in patients with PL vs non-syndromic, obesity associated NAFLD (NAFLD). Methods Single-center retrospective analysis of subjects with NAFLD (N=73) and PL (N=28). Fibroscan Controlled Attenuated Parameter (CAP) was used to estimate liver fat. A1c, β-hydroxybutyrate, and circulating lipids by NMR were measured simultaneously and within 6 months of CAP measurement. Insulin resistance was estimated by HOMA-IR (fasting glucose x insulin ÷ 405) and LP-IR (a lipoprotein-based measure of IR derived from circulating lipid particles). Results The PL group was 86% female vs 48% in NAFLD (P<0.001) and younger (43±8 vs. 50±14 years, P<0.03). BMI was lower PL vs NAFLD (27±6 vs 33±6 kg/m2, P<0.0001). Fasting insulin was not statistically different between PL and NAFLD (median 26.4 [interquartile range 21.3,51.2]) vs 31.6 mcU/L [15.1-33.4], P=0.052); however, IR was more severe in PL vs NAFLD based on both HOMA-IR (15.5±16.2 vs 7.6±5.2, P=0.003) and LP-IR (65.1±19.3 vs 58.5±16.7, P=0.03). A1c was higher in PL (7.5±2.1 vs 5.9±0.8%, <0.001). CAP was similar in PL and NAFLD (301±57 vs 320±49 dB/m, P=0.1). CAP correlated with HOMA-IR in both PL (r=0.51, p=0.01) and NAFLD (r=0.44, p=0.003), but for any given HOMA-IR liver fat was lower in PL vs NAFLD. FFA levels were comparable between groups (0.52± 0.28 vs 0.50±0.27 mEq/L, P=0.058). TRLP concentration by NMR was higher in PL compared to NAFLD (240±123 vs165±86 nmol/L, p=0.001) as was β-hydroxybutyrate (162±67 vs 115±58 mmol/L, P=0.004). Conclusions Patients with PL have comparable liver fat vs. non-syndromic NAFLD despite worse insulin resistance. To understand the lower liver fat relative to insulin resistance in PL, we examined input, oxidation, and export of lipid from the liver. Surprisingly, despite lower adipose mass in PL vs NAFLD, FFA input to the liver was similar. Hepatic fat oxidation and export, estimated by β-hydroxybutyrate and large VLDL respectively, were both higher in PL. This suggests a shift of fat storage out of the liver into the circulation in PL. Presentation: Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.