title: Leucine restores murine hepatic triglyceride accumulation induced by a low-protein diet by suppressing autophagy and excessive endoplasmic reticulum stress.
abstract: Although it is known that a low-protein diet induces hepatic triglyceride (TG) accumulation in both rodents and humans, little is known about the underlying mechanism. In the present study, we modeled hepatic TG accumulation by inducing dietary protein deficiency in mice and aimed to determine whether certain amino acids could prevent low-protein diet-induced TG accumulation in the mouse liver. Mice fed a diet consisting of 3 % casein (3C diet) for 7 days showed hepatic TG accumulation with up-regulation of TG synthesis for the Acc gene and down-regulation of TG-rich lipoprotein secretion from hepatocytes for Mttp genes. Supplementing the 3 % casein diet with essential amino acids, branched-chain amino acids, or the single amino acid leucine rescued hepatic TG accumulation. In the livers of mice fed the 3 % casein diet, we observed a decrease in the levels of the autophagy substrate p62, an increase in the expression levels of the autophagy marker LC3-II, and an increase in the splicing of the endoplasmic reticulum (ER) stress-dependent Xbp1 gene. Leucine supplementation to the 3 % casein diet did not affect genes related to lipid metabolism, but inhibited the decrease in p62, the increase in LC3-II, and the increase in Xbp1 splicing levels in the liver. Our results suggest that ER stress responses and activated autophagy play critical roles in low-protein diet-induced hepatic TG accumulation in mice, and that leucine suppresses these two major protein degradation systems. This study contributes to understanding the mechanisms of hepatic disorders of lipid metabolism.
authors.affiliation: Laboratory of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480, Japan.|Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, Tokyo, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Yokota
authors.affiliation: Laboratory of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Ando
authors.affiliation: Laboratory of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Aoyama
authors.affiliation: Laboratory of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480, Japan.
authors.forename: Kawai
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Laboratory of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480, Japan. shibatas@waseda.jp.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Shibata
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002364:Caseins / Q000008:administration & dosage / Q000378:metabolism; D018753:Diet, Protein-Restricted; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005526:Food, Formulated; D005786:Gene Expression Regulation; D006801:Humans; D007930:Leucine / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D011488:Protein Deficiency / Q000178:diet therapy* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D002364:Caseins; C490981:Gtf2h1 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D014157:Transcription Factors; D014280:Triglycerides; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C106092:microsomal triglyceride transfer protein; D051758:Transcription Factor TFIIH; D000103:Acetyl-CoA Carboxylase; D007930:Leucine
keywords: Autophagy; ER stress; Fatty liver; Metabolic syndrome; Unfolded protein response