Metabolic alterations of lipid kinetics in NAFLD patients and their contribution to liver damage.

Background and aims: Excessive lipids availability contributes to the necroinflammatory processes and to fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). The purpose of this study was to evaluate the impact of whole body lipolysis, circulating NEFA levels/composition and insulin resistance (IR), during an oral fat load, in the pathogenesis of liver damage in NAFLD. Methods: [2H5]glycerol kinetics and plasma levels of Fatty acids (FA), triglycerides (TG) and VLDL-TG, saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) were determined in 15 non-obese patients with biopsy-proven NAFLD and 6 controls during an oral fat load. FA composition was assessed by high performance liquid chromatography. Total and incremental post-load area under the curve (AUC and IAUC) were calculated. Whole body lipolysis and Adipose tissue IR index were derived from glycerol Ra. Results: NAFLD patients compared to controls, had higher TG, VLDLTG and FA levels at all curve time-points (p=0.029, p=0.038 and p=0.036 respectively); similarly, the corresponding IAUCs resulted increased 2-fold (p=0.024, p=0.024 and p=0.022). NAFLD patients had similar levels of SFA, MUFA and PUFA in the basal state, but increased SFA (lauric and myristic acids, p=0.009 and 0.031) and MUFA (oleic acid, p=0.023) after load. Basal glycerol Ra and Adipo-IR were significantly increased in NAFLD patients (p<0.03 and p<0.001). Factors associated with severe fibrosis were higher BMI (p=0.007), IAUC insulin (p=0.038), IAUC C-peptide (p=0.013) and both basal and post-load Adipo-IR (p=0.033 and 0.007) while only BMI (p=0.05), IAUC insulin (p=0.05) and IAUC C-peptide (p=0.027) were associated with a NAS score≥5. Conclusions: NAFLD patients present multiple qualitative and quantitative alterations in lipid metabolism even in the absence of overt metabolic derangements. Adipo-IR is one of the main determinants of liver fibrosis, but an important contribution is provided by insulin levels and secretion per se.