Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease

Objectives In non-alcoholic fatty liver disease (NAFLD), hepatic steatosis is intricately linked with a number of metabolic alterations. We studied substrate utilisation in NAFLD during basal, insulin-stimulated and exercise conditions, and correlated these outcomes with disease severity. Methods 20 patients with NAFLD (meanSD body mass index (BMI) 34.16.7kg/m(2)) and 15 healthy controls (BMI 23.4 +/- 2.7kg/m(2)) were assessed. Respiratory quotient (RQ), whole-body fat (Fat(ox)) and carbohydrate (CHOox) oxidation rates were determined by indirect calorimetry in three conditions: basal (resting and fasted), insulin-stimulated (hyperinsulinaemic-euglycaemic clamp) and exercise (cycling at an intensity to elicit maximal Fat(ox)). Severity of disease and steatosis were determined by liver histology, hepatic Fat(ox) from plasma -hydroxybutyrate concentrations, aerobic fitness expressed as (V) over dotO(2 peak), and visceral adipose tissue (VAT) measured by computed tomography. Results Within the overweight/obese NAFLD cohort, basal RQ correlated positively with steatosis (r=0.57, p=0.01) and was higher (indicating smaller contribution of Fat(ox) to energy expenditure) in patients with NAFLD activity score (NAS) 5 vs <5 (p=0.008). Both results were independent of VAT, % body fat and BMI. Compared with the lean control group, patients with NAFLD had lower basal whole-body Fat(ox) (1.2 +/- 0.3 vs 1.5 +/- 0.4 mg/kgFFM/min, p=0.024) and lower basal hepatic Fat(ox) (ie, -hydroxybutyrate, p=0.004). During exercise, they achieved lower maximal Fat(ox) (2.5 +/- 1.4 vs. 5.8 +/- 3.7 mg/kgFFM/min, p=0.002) and lower (V) over dotO(2 peak) (p<0.001) than controls. Fat(ox) during exercise was not associated with disease severity (p=0.79). Conclusions Overweight/obese patients with NAFLD had reduced hepatic Fat(ox) and reduced whole-body Fat(ox) under basal and exercise conditions. There was an inverse relationship between ability to oxidise fat in basal conditions and histological features of NAFLD including severity of steatosis and NAS.