High protein intake reduces intrahepatocellular lipid deposition in humans

Background: High sugar and fat intakes are known to increase intrahepatocellular lipids (IHCLs) and to cause insulin resistance. High protein intake may facilitate weight loss and improve glucose homeostasis in insulin-resistant patients, but its effects on IHCLs remain unknown. Objective: The aim was to assess the effect of high protein intake on high-fat diet--induced IHCL accumulation and insulin sensitivity in healthy young men. Design: Ten volunteers were studied in a crossover design after 4 d of either a hypercaloric high-fat (HF) diet; a hypercaloric high-fat, high-protein (HFHP) diet; or a control, isocaloric (control) diet. IHCLs were measured by [sup.1]H-magnetic resonance spectroscopy, fasting metabolism was measured by indirect calorimetry, insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp, and plasma concentrations were measured by enzyme-linked immunosorbent assay and gas chromatography--mass spectrometry; expression of key lipogenic genes was assessed in subcutaneous adipose tissue biopsy specimens. Results: The HF diet increased IHCLs by 90 [+ or -] 26% and plasma tissue-type plasminogen activator inhibitor-1 (tPAI-1) by 54 [+ or -] 11% (P < 0.02 for both) and inhibited plasma free fatty acids by 26 [+ or -] 11% and [beta]-hydroxybutyrate by 61 [+ or -] 27% (P < 0.05 for both). The HFHP diet blunted the increase in IHCLs and normalized plasma [beta]-hydroxybutyrate and tPAI-I concentrations. Insulin sensitivity was not altered, whereas the expression of sterol regulatory element-binding protein-1c and key lipogenic genes increased with the HF and HFHP diets (P < 0.02). Bile acid concentrations remained unchanged after the HF diet but increased by 50 [+ or -] 24% after the HFHP diet (P = 0.14). Conclusions: Protein intake significantly blunts the effects of an HF diet on IHCLs and tPAI-1 through effects presumably exerted at the level of the liver. Protein-induced increases in bile acid concentrations may be involved. This trial was registered at www.clinicaltrials.gov as NCT00523562.