Low-Density Lipoprotein Receptor Signaling Mediates the Triglyceride-Lowering Action of Akkermansia muciniphila in Genetic-Induced Hyperlipidemia

Jing Shen, Xuedong Tong, Neetu Sud, Rituraj Khound, Yongyan Song, Maria X. Maldonado-Gomez, Jens Walter, Qiaozhu Su

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Objective-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. Approach and Results-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. Conclusions-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.

Original languageEnglish (US)
Pages (from-to)1448-1456
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume36
Issue number7
DOIs
StatePublished - Jul 1 2016

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LDL Receptors
Hyperlipidemias
Triglycerides
Carrier Proteins
IDL Lipoproteins
Chylomicrons
Endoplasmic Reticulum Stress
Apolipoproteins E
Lipoproteins
Insulin Resistance
Gastrointestinal Tract
Liver
Chylomicron Remnants
Inflammation
Bacteria
Apolipoproteins
Hypertriglyceridemia
Mucins
Mucus
Hepatocytes

Keywords

  • Gut microbiota
  • Hyperlipidemia
  • Intermediate-density lipoproteins
  • Low-density lipoprotein receptor
  • Toll-like receptor 4
  • Triglyceride
  • chylomicrons

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Low-Density Lipoprotein Receptor Signaling Mediates the Triglyceride-Lowering Action of Akkermansia muciniphila in Genetic-Induced Hyperlipidemia. / Shen, Jing; Tong, Xuedong; Sud, Neetu; Khound, Rituraj; Song, Yongyan; Maldonado-Gomez, Maria X.; Walter, Jens; Su, Qiaozhu.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 36, No. 7, 01.07.2016, p. 1448-1456.

Research output: Contribution to journalArticle

Shen, Jing ; Tong, Xuedong ; Sud, Neetu ; Khound, Rituraj ; Song, Yongyan ; Maldonado-Gomez, Maria X. ; Walter, Jens ; Su, Qiaozhu. / Low-Density Lipoprotein Receptor Signaling Mediates the Triglyceride-Lowering Action of Akkermansia muciniphila in Genetic-Induced Hyperlipidemia. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2016 ; Vol. 36, No. 7. pp. 1448-1456.
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abstract = "Objective-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. Approach and Results-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. Conclusions-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.",
keywords = "Gut microbiota, Hyperlipidemia, Intermediate-density lipoproteins, Low-density lipoprotein receptor, Toll-like receptor 4, Triglyceride, chylomicrons",
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AU - Tong, Xuedong

AU - Sud, Neetu

AU - Khound, Rituraj

AU - Song, Yongyan

AU - Maldonado-Gomez, Maria X.

AU - Walter, Jens

AU - Su, Qiaozhu

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KW - Intermediate-density lipoproteins

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KW - Triglyceride

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