title: LGR4 acts as a link between the peripheral circadian clock and lipid metabolism in liver.
abstract: The circadian clock plays an important role in the liver by regulating the major aspects of energy metabolism. Currently, it is assumed that the circadian clock regulates metabolism mostly by regulating the expression of liver enzymes at the transcriptional level, but the underlying mechanism is not well understood. In this study, we showed that Lgr4 homozygous mutant (Lgr4(m/m)) mice showed alteration in the rhythms of the respiratory exchange ratio. We further detected impaired plasma triglyceride rhythms in Lgr4(m/m) mice. Although no significant changes in plasma cholesterol rhythms were observed in the Lgr4(m/m) mice, their cholesterol levels were obviously lower. This phenotype was further confirmed in the context of ob/ob mice, in which lack of LGR4 dampened circadian rhythms of triglyceride. We next demonstrated that Lgr4 expression exhibited circadian rhythms in the liver tissue and primary hepatocytes in mice, but we did not detect changes in the expression levels or circadian rhythms of classic clock genes, such as Clock, Bmal1 (Arntl), Pers, Rev-erbs, and Crys, in Lgr4(m/m) mice compared with their littermates. Among the genes related to the lipid metabolism, we found that the diurnal expression pattern of the Mttp gene, which plays an important role in the regulation of plasma lipid levels, was impaired in Lgr4(m/m) mice and primary Lgr4(m/m) hepatocytes. Taken together, our results demonstrate that LGR4 plays an important role in the regulation of plasma lipid rhythms, partially through regulating the expression of microsomal triglyceride transfer protein. These data provide a possible link between the peripheral circadian clock and lipid metabolism.
authors.affiliation: Laboratory for Endocrine and Metabolic Diseases, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrinology and Metabolism, Shanghai Key Laboratory for Endocrine Tumors and E-Institute of Shanghai Universities, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Jiqiu
authors.initials: J
authors.lastname: Wang
authors.forename: Maopei
authors.initials: M
authors.lastname: Chen
authors.forename: Nengguang
authors.initials: N
authors.lastname: Fan
authors.forename: Qinyun
authors.initials: Q
authors.lastname: Ma
authors.forename: Ruixin
authors.initials: R
authors.lastname: Liu
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Li
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D057906:Circadian Clocks / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D020738:Leptin / Q000172:deficiency / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012119:Respiration
chemical_list: D002352:Carrier Proteins; C496200:LGR4 protein, mouse; D020738:Leptin; D008055:Lipids; D043562:Receptors, G-Protein-Coupled; C106092:microsomal triglyceride transfer protein
keywords: G protein-coupled receptor; circadian rhythm; lipid metabolism; respiratory exchange ratio