title: Low-Density Lipoprotein Receptor Signaling Mediates the Triglyceride-Lowering Action of Akkermansia muciniphila in Genetic-Induced Hyperlipidemia.
abstract: Akkermansia muciniphila (A muciniphila) is a mucin-degrading bacterium that resides in the mucus layer whose abundance inversely correlates with body weight and the development of diabetes mellitus in mice and humans. The objective of this study was to explore the regulatory effect of A muciniphila on host lipoprotein metabolism, insulin sensitivity, and hepatic metabolic inflammation.
  
  
  
  By establishing a novel mouse model that colonized the A muciniphila in the gastrointestinal tract of the cAMP-responsive binding protein H (CREBH)-deficient mouse and in vivo chylomicron assay, we found that increased colonization of A muciniphila in the gastrointestinal tract of wild-type mice protected mice from an acute fat load-induced hyperlipidemia compared with vehicle-treated mice. A muciniphila administration also significantly ameliorated chronic hypertriglyceridemia, improved insulin sensitivity, and prevented overproduction of postprandial chylomicrons in CREBH-null mice. Mechanistic studies revealed that increased A muciniphila colonization induced expression of low-density lipoprotein receptors and apolipoprotein E in the hepatocytes of CREBH-null mice, which facilitated the uptake of intermediate-density lipoprotein via the mediation of apolipoprotein B100 and apolipoprotein E, leading to the increased clearance of triglyceride-rich lipoprotein remnants, chylomicron remnants, and intermediate-density lipoproteins, from the circulation. Treatment with A muciniphila further improved hepatic endoplasmic reticulum stress and metabolic inflammation in CREBH-null mice.
  
  
  
  Increased colonization of the disease-protective gut bacteria A muciniphila protected the host from acute and chronic hyperlipidemia by enhancing the low-density lipoprotein receptor expression and alleviating hepatic endoplasmic reticulum stress and the inflammatory response in CREBH-null mice.
authors.affiliation: From the Departments of Nutrition and Health Sciences (J.S., X.T., N.S., R.K., Y.S., Q.S.) and Food Science and Technology (M.X.M.-G.), University of Nebraska-Lincoln; and Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Canada (J.W.).
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.affiliation: From the Departments of Nutrition and Health Sciences (J.S., X.T., N.S., R.K., Y.S., Q.S.) and Food Science and Technology (M.X.M.-G.), University of Nebraska-Lincoln; and Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Canada (J.W.).
authors.forename: Xuedong
authors.initials: X
authors.lastname: Tong
authors.affiliation: From the Departments of Nutrition and Health Sciences (J.S., X.T., N.S., R.K., Y.S., Q.S.) and Food Science and Technology (M.X.M.-G.), University of Nebraska-Lincoln; and Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Canada (J.W.).
authors.forename: Neetu
authors.initials: N
authors.lastname: Sud
authors.affiliation: From the Departments of Nutrition and Health Sciences (J.S., X.T., N.S., R.K., Y.S., Q.S.) and Food Science and Technology (M.X.M.-G.), University of Nebraska-Lincoln; and Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Canada (J.W.).
authors.forename: Rituraj
authors.initials: R
authors.lastname: Khound
authors.affiliation: From the Departments of Nutrition and Health Sciences (J.S., X.T., N.S., R.K., Y.S., Q.S.) and Food Science and Technology (M.X.M.-G.), University of Nebraska-Lincoln; and Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Canada (J.W.).
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Song
authors.affiliation: From the Departments of Nutrition and Health Sciences (J.S., X.T., N.S., R.K., Y.S., Q.S.) and Food Science and Technology (M.X.M.-G.), University of Nebraska-Lincoln; and Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Canada (J.W.).
authors.forename: Maria X
authors.initials: MX
authors.lastname: Maldonado-Gomez
authors.affiliation: From the Departments of Nutrition and Health Sciences (J.S., X.T., N.S., R.K., Y.S., Q.S.) and Food Science and Technology (M.X.M.-G.), University of Nebraska-Lincoln; and Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Canada (J.W.).
authors.forename: Jens
authors.initials: J
authors.lastname: Walter
authors.affiliation: From the Departments of Nutrition and Health Sciences (J.S., X.T., N.S., R.K., Y.S., Q.S.) and Food Science and Technology (M.X.M.-G.), University of Nebraska-Lincoln; and Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Canada (J.W.). qsu2@unl.edu.
authors.forename: Qiaozhu
authors.initials: Q
authors.lastname: Su
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D002914:Chylomicrons / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress; D000069196:Gastrointestinal Microbiome; D041981:Gastrointestinal Tract / Q000382:microbiology*; D020022:Genetic Predisposition to Disease; D054884:Host-Pathogen Interactions; D015228:Hypertriglyceridemia / Q000097:blood / Q000235:genetics / Q000382:microbiology / Q000517:prevention & control*; D007333:Insulin Resistance; D053419:Lipoproteins, IDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000382:microbiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011973:Receptors, LDL / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014280:Triglycerides / Q000097:blood*; D061327:Verrucomicrobia / Q000502:physiology*
chemical_list: D053299:Apolipoprotein B-100; D001057:Apolipoproteins E; D015415:Biomarkers; D002914:Chylomicrons; C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D053419:Lipoproteins, IDL; D011973:Receptors, LDL; D014280:Triglycerides
keywords: chylomicrons; gut microbiota; hyperlipidemia; intermediate-density lipoproteins; low-density lipoprotein receptor; toll-like receptor 4; triglyceride