Inhibition of Beta-Oxidation Improves Hepatic Steatosis and Metabolism in Obese Non-Diabetic Humans.

Borra, Ronald; Maggio, Romina; Kankaanpää, Mikko; Parkkola, Riitta; Naum, Alexandru; Tuunanen, Helena; Någren, Kjell; Viljanen, Tapio; Ferrannini, Ele; Nuutila, Pirjo; Iozzo, Patricia

The metabolic consequences of alterations in fatty acid oxidation remain controversial. Treatment with the partial beta-oxidation inhibitor trimetazidine improves the glycemic profile in subjects with cardiovascular disease and diabetes, and has been shown to reduce liver fat content in perfused rat organs. The aim of the study was to investigate the effects of partial beta-oxidation inhibition on liver metabolism and fat content in humans. Nine non-diabetic, moderately obese subjects (BMI 31±1 kg/m2) were studied before and after one-month treatment with trimetazidinc. Liver fat content (LFC) and visceral fat mass (VFM) were measured by Magnetic Resonance Spectroscopy and Imaging, respectively. Positron Emission Tomography (PET) with 11C-palmitate and 18F-FDG was used to quantify fasting rates of liver fatty acid (LFU) and glucose uptake (LGU); systemic glucose appearance and lipolytic rates were estimated from the plasma kinetics of the PET tracers. Treatment with trimetszidinc reduced liver enzymes (ALAT, - 18±5%, p-=0.018, ASAT,-8±3%, p=045),BMI (-2-4±1%, p=0.047), and HbA1c (-3±1%, p--0.06). No change occurred in VFM, and fasting endogenous glucose production. LFC decreased by 33% (median, p=0.012), and LGU increased by 40% (median, p=0.04). LFU and systemic lipolysis were slightly but non-significantly up-regulated, and their changes were strongly correlated (r=0.95, p<0.0001). The decline in LFC was significantly associated with changes in circulating triglyceride levels (r=0.83, 0.006), and in lipolysis (r=0.66, p=0.049). The enhancement in LGU tended to inversely correlate with changes in lipolysis (r=-0.57, p=0.11), VFM (r=-0.65, 0.058), and HbA1c (r=-0.54, p=0.17). In non-diabetic obese individuals, the sustained partial inhibition of beta-oxidation reduces hepatic steatosis and enzymes in a significant manner, and strongly promotes liver glucose uptake, resulting in improved glucose control. Systemic lipolysis appears as common correlate of hepatic metabolic rates and fat content.

PHYSIOLOGICAL oxidation; FATTY degeneration; METABOLISM; OVERWEIGHT persons; FATTY acids; FATTY liver; DIABETES

Diabetes, 2007, Vol 56, pA393

0012-1797

Academic Journal