title: High-protein diets prevent steatosis and induce hepatic accumulation of monomethyl branched-chain fatty acids.
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 Ppargc1α (+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.
authors.affiliation: Department of Anatomy & Embryology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, the Netherlands.
authors.forename: Sonia C
authors.initials: SC
authors.lastname: Garcia Caraballo
authors.affiliation: Department of Anatomy & Embryology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, the Netherlands; Nutrigenomics Consortium, Top Institute of Food and Nutrition, Wageningen, the Netherlands.
authors.forename: Tine M
authors.initials: TM
authors.lastname: Comhair
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.affiliation: Department of General Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, the Netherlands.
authors.forename: Cornelis H C
authors.initials: CH
authors.lastname: Dejong
authors.affiliation: Department of Anatomy & Embryology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, the Netherlands; Tytgat Institute for Liver and Gastrointestinal Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Nutrigenomics Consortium, Top Institute of Food and Nutrition, Wageningen, the Netherlands.
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Lamers
authors.affiliation: Department of Anatomy & Embryology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, the Netherlands. Electronic address: leo.koehler@maastrichtuniversity.nl.
authors.forename: S Eleonore
authors.initials: SE
authors.lastname: Koehler
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects; D018753:Diet, Protein-Restricted; D004041:Dietary Fats / Q000008:administration & dosage*; D004044:Dietary Proteins / Q000008:administration & dosage*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000517:prevention & control*; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood; D005934:Glucagon / Q000097:blood; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010169:Palmitic Acids / Q000097:blood; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010743:Phospholipids / Q000097:blood; D012737:Sex Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D004044:Dietary Proteins; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D020738:Leptin; D010169:Palmitic Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010743:Phospholipids; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D014280:Triglycerides; C414620:fibroblast growth factor 21; C046143:14-methylhexadecanoic acid; D005346:Fibroblast Growth Factors; D005934:Glucagon; D002784:Cholesterol
keywords: Branched-chain amino acids; Branched-chain keto acids; Fatty acid composition; Fatty liver; High-protein diet