title: Dietary phosphate restriction induces hepatic lipid accumulation through dysregulation of cholesterol metabolism in mice.
abstract: Excessive inorganic phosphate (Pi) intake and hyperphosphatemia have both been speculated to be risk factors for cardiovascular disease and hypercholesterolemia, and dysregulation of cholesterol metabolism can lead to atherosclerosis. However, the relationship between Pi and cholesterol metabolism has not been investigated in detail. Our recent study showed that triiodothyronine can induce both hyperphosphatemia and hypocholesterolemia in mice. We therefore hypothesized a possible linkage between Pi and cholesterol metabolism. In this study, we investigated the effects of dietary Pi intake on cholesterol metabolism in mice. Mice were divided into 4 groups, which were fed diets containing 1.2% or 0.1% Pi and with or without 2% cholesterol (Pi-sufficient, Pi-restricted, Pi-sufficient + Chol, and Pi-restricted + Chol), for 12 days. Inorganic phosphate-restricted mice exhibited significantly higher liver weights than did Pi-sufficient mice. Interestingly, dietary Pi restriction significantly increased high-cholesterol diet-induced hepatic lipid accumulation. Real-time polymerase chain reaction analysis revealed that dietary Pi restriction decreased expression of hepatic genes involved in cholesterol metabolism and fatty acid biosynthesis. In addition, hepatic messenger RNA levels of several transcription factors including peroxisome proliferator-activated receptors and liver X receptor were markedly decreased by Pi restriction. Furthermore, plasma lipid and lipoprotein profile analysis showed that dietary Pi restriction reduced susceptibility to high-cholesterol diet-induced hyperlipidemia. Importantly, we found that there was a significant negative correlation between plasma levels of Pi and total cholesterol. These results suggest that dietary Pi plays an important role in the development of fatty liver disease and hyperlipidemia induced by a high-cholesterol diet through regulation of lipid metabolism-related gene expression in the liver.
authors.affiliation: Department of Clinical Nutrition, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan.
authors.forename: Sarasa
authors.initials: S
authors.lastname: Tanaka
authors.forename: Hironori
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Otoki
authors.initials: O
authors.lastname: Nakahashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kagawa
authors.forename: Mariko
authors.initials: M
authors.lastname: Ishiguro
authors.forename: Masashi
authors.initials: M
authors.lastname: Masuda
authors.forename: Mina
authors.initials: M
authors.lastname: Kozai
authors.forename: Shoko
authors.initials: S
authors.lastname: Ikeda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Taketani
authors.forename: Eiji
authors.initials: E
authors.lastname: Takeda
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000009:adverse effects / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000009:adverse effects / Q000378:metabolism; D004032:Diet; D005227:Fatty Acids / Q000096:biosynthesis; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D015870:Gene Expression; D005786:Gene Expression Regulation; D006949:Hyperlipidemias / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism; D010710:Phosphates / Q000097:blood / Q000172:deficiency / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002791:Cholesterol, Dietary; D005227:Fatty Acids; C000717428:Fgf23 protein, mouse; D008055:Lipids; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D010710:Phosphates; D012333:RNA, Messenger; D014157:Transcription Factors; D000089703:Fibroblast Growth Factor-23; D002784:Cholesterol
keywords: 1,25(OH)(2)D(3); 1,25-dihydroxyvitamin D(3); 3-hydroxy-3-methyl-glutaryl-CoA reductase; CKD; CVD; CYP7A1; Cholesterol; Dietary phosphate; FGF-23; FXR; Fatty liver; Gene expression; HDL; HMGC-R; HSL; LDL; LDL-R; LXR; Mice; Npt2a; PPARα; PPARγ; Pi; SCD1; TG; VLDL; cardiovascular disease; cholesterol 7-α-monooxygenase or cytochrome P450 7A1; chronic kidney disease; farnesoid X receptor; fibroblast growth factor-23; high-density lipoprotein; hormone-sensitive lipase; inorganic phosphate; liver X receptor; low-density lipoprotein; low-density lipoprotein receptor; peroxisome proliferator–activated receptor α; peroxisome proliferator–activated receptor γ; stearoyl-CoA desaturase-1; triglyceride; type IIa sodium-dependent phosphate cotransporter; very low density lipoprotein