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 (mean ± SD body mass index (BMI) 34.1 ± 6.7 kg/m²) and 15 healthy controls (BMI 23.4 ± 2.7 kg/m²) were assessed. Respiratory quotient (RQ), whole-body fat (Fat_ox) and carbohydrate (CHO_ox) 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 β-hydroxybutyrate concentrations, aerobic fitness expressed as V·_O2 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, β-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·_O2 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.