High-protein diets prevent steatosis and induce hepatic accumulation of monomethyl branched-chain fatty acids

S. Garcia Caraballo, T.M. Comhair, S.M. Houten, C.H. Dejong, W.H. Lamers, S.E. Koehler

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The hallmark of nonalcoholic fatty liver disease is steatosis of unknown etiology. To test how dietary protein decreases steatosis, we fed female C57BL/6 J mice low-fat (8 en%) or high-fat (42 en%) combined with low-protein (11 en%), high-protein (HP; 35 en%) or extra-high-protein (HPX; 58 en%) diets for 3 weeks. The 35 en% protein diets reduced hepatic triglyceride, free fatty acid, cholesterol and phospholipid contents to ~50% of that in 11 en% protein diets. Every additional 10 en% protein reduced hepatic fat content ~1.5 g%. HP diets had no effect on lipogenic or fatty acid-oxidizing genes except Ppargc1alpha (+30%), increased hepatic PCK1 content 3- to 5-fold, left plasma glucose and hepatic glycogen concentration unchanged, and decreased inflammation and cell stress (decreased Fgf21 and increased Gsta expression). The HP-mediated decrease in steatosis correlated inversely with plasma branched-chain amino-acid (BCAA) concentrations and hepatic content of BCAA-derived monomethyl branched-chain fatty acids (mmBCFAs) 14-methylpentadecanoic (14-MPDA; valine-derived) and, to a lesser extent, 14-methylhexadecanoic acid (isoleucine-derived). Liver lipid content was 1.6- to 1.8-fold higher in females than in males, but the anti-steatotic effect of HP diets was equally strong. The strong up-regulation of PCK1 and literature data showing an increase in phosphoenolpyruvate and a decline in tricarboxylic acid cycle intermediates in liver reveal that an increased efflux of these intermediates from mitochondria represents an important effect of an HP diet. The HP diet-induced increase in 14-MPDA and the dietary response in gene expression were more pronounced in females than males. Our findings are compatible with a facilitating role of valine-derived mmBCFAs in the antisteatotic effect of HP diets.
Original languageEnglish
Pages (from-to)1263-1274
Number of pages12
JournalJournal of Nutritional Biochemistry
Volume25
Issue number12
DOIs
Publication statusPublished - Dec 2014

Keywords

  • High-protein diet
  • Fatty liver
  • Fatty acid composition
  • Branched-chain keto acids
  • Branched-chain amino acids
  • GROWTH-FACTOR 21
  • IMPROVES INSULIN SENSITIVITY
  • ACTIVATED RECEPTOR-ALPHA
  • HIGH-CARBOHYDRATE DIET
  • INDUCED OBESE MICE
  • LIVER-DISEASE
  • AMINO-ACIDS
  • SEX-DIFFERENCES
  • NONALCOHOLIC STEATOHEPATITIS
  • ENERGY-EXPENDITURE

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