Abstract
The biogenesis of high-density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most of the HDL in the blood, HDL synthesis also occurs in the small intestine. Here, we show that intestine-derived HDL traverses the portal vein in the HDL3 subspecies form, in complex with lipopolysaccharide (LPS)-binding protein (LBP). HDL3, but not HDL2 or low-density lipoprotein, prevented LPS binding to and inflammatory activation of liver macrophages and instead supported extracellular inactivation of LPS. In mouse models involving surgical, dietary, or alcoholic intestinal insult, loss of intestine-derived HDL worsened liver injury, whereas outcomes were improved by therapeutics that elevated and depended upon raising intestinal HDL. Thus, protection of the liver from injury in response to gut-derived LPS is a major function of intestinally synthesized HDL.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute-Phase Proteins / metabolism
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Adult
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Animals
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Carrier Proteins / metabolism
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Cholesterol, HDL / blood
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Cholesterol, HDL / metabolism
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Enterocytes / metabolism
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Humans
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Intestine, Small / metabolism*
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Intestine, Small / surgery
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Kupffer Cells / immunology
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Kupffer Cells / metabolism
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Lipopolysaccharide Receptors / metabolism
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Lipopolysaccharides / metabolism
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Lipoproteins, HDL3 / blood
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Lipoproteins, HDL3 / metabolism*
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Liver / metabolism*
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Liver / pathology
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Liver Cirrhosis / pathology
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Liver Cirrhosis / prevention & control
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Liver Diseases / pathology
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Liver Diseases / prevention & control*
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Liver X Receptors / metabolism
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Portal Vein / metabolism*
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Protein Binding
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Signal Transduction
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Toll-Like Receptor 4 / metabolism
Substances
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Acute-Phase Proteins
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Carrier Proteins
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Cholesterol, HDL
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Lipopolysaccharide Receptors
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Lipopolysaccharides
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Lipoproteins, HDL3
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Liver X Receptors
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Membrane Glycoproteins
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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lipopolysaccharide-binding protein