LDL Receptor Signaling Mediates the Triglyceride-lowering Action of Akkermansia Muciniphila in Genetic Induced Hyperlipidemia

Jing Shen, Qiaozhu Su

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56 Citations (Scopus)

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 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(GI) 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 GI tract of wild-type mice protected mice from an acute fat load-induced hyperlipidemia compared to vehicle-treated mice. A. muciniphila administration also significantly ameliorated chronic hypertriglyceridemia, improved insulin sensitivity and prevented overproduction of postprandial chylomicrons in the CREBH-null mice. Mechanistic studies revealed that increased A. muciniphila colonization induced expression of low density lipoprotein (LDL) receptors and apolipoprotein E (apoE) in the hepatocytes of CREBH-null mice, which facilitated the uptake of intermediate density lipoprotein (IDL) via the mediation of apolipoprotein B100 (apoB) and apoE, leading to the increased clearance of triglyceride-rich very-low-density lipoprotein (VLDL) particles, the precursors of IDLs, from the circulation. Treatment with A. muciniphila further improved hepatic ER stress and metabolic inflammation in CREBH-null mice.
Conclusion: Increased colonization of the disease-protective gut bacteria A. muciniphila protected the host from acute and chronic hyperlipidemia by enhancing the LDL receptor expression and alleviating hepatic ER stress and the inflammatory response in CREBH-null mice.
Original languageEnglish
Pages (from-to)A398
Number of pages1
JournalArteriosclerosis Thrombosis and Vascular Biology
Volume36
Issue numbersuppl_1
Publication statusPublished - 09 Feb 2016

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