title: Prevention and reversal of hepatic steatosis with a high-protein diet in mice.
abstract: The hallmark of NAFLD is steatosis of unknown etiology. We tested the effect of a high-protein (HP)(2) diet on diet-induced steatosis in male C57BL/6 mice with and without pre-existing fatty liver. Mice were fed all combinations of semisynthetic low-fat (LF) or high-fat (HF) and low-protein (LP) or HP diets for 3weeks. To control for reduced energy intake by HF/HP-fed mice, a pair-fed HF/LP group was included. Reversibility of pre-existing steatosis was investigated by sequentially feeding HF/LP and HF/HP diets. HP-containing diets decreased hepatic lipids to ~40% of corresponding LP-containing diets, were more efficient in this respect than reducing energy intake to 80%, and reversed pre-existing diet-induced steatosis. Compared to LP-containing diets, mice fed HP-containing diets showed increased mitochondrial oxidative capacity (elevated Pgc1α, mAco, and Cpt1 mRNAs, complex-V protein, and decreased plasma free and short-chain acyl-carnitines, and [C0]/[C16+C18] carnitine ratio); increased gluconeogenesis and pyruvate cycling (increased PCK1 protein and fed plasma-glucose concentration without increased G6pase mRNA); reduced fatty-acid desaturation (decreased Scd1 expression and [C16:1n-7]/[C16:0] ratio) and increased long-chain PUFA elongation; a selective increase in plasma branched-chain amino acids; a decrease in cell stress (reduced phosphorylated eIF2α, and Fgf21 and Chop expression); and a trend toward less inflammation (lower Mcp1 and Cd11b expression and less phosphorylated NFκB).
  
  
  CONCLUSIONS
  HP diets prevent and reverse steatosis independently of fat and carbohydrate intake more efficiently than a 20% reduction in energy intake. The effect appears to result from fuel-generated, highly distributed small, synergistic increases in lipid and BCAA catabolism, and a decrease in cell stress.
authors: Department of Anatomy & Embryology, Maastricht University, Maastricht, The Netherlands. sonia.garcia@maastrichtuniversity.nl
authors: Sonia C
authors: SC
authors: Garcia-Caraballo
authors: Tine M
authors: TM
authors: Comhair
authors: Fons
authors: F
authors: Verheyen
authors: Ingrid
authors: I
authors: Gaemers
authors: Frank G
authors: FG
authors: Schaap
authors: Sander M
authors: SM
authors: Houten
authors: Theodorus B M
authors: TB
authors: Hakvoort
authors: Cornelis H C
authors: CH
authors: Dejong
authors: Wouter H
authors: WH
authors: Lamers
authors: S Eleonore
authors: SE
authors: Koehler
mesh_terms: D000596:Amino Acids / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004044:Dietary Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D004041:Dietary Fats; D004044:Dietary Proteins; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D002784:Cholesterol; D038762:Ribosomal Protein S6 Kinases, 70-kDa