Enterically derived high-density lipoprotein restrains liver injury through the portal vein
Intestinal HDL is hepatoprotective
High-density lipoprotein (HDL) is important for cholesterol metabolism and may have anti-inflammatory and antimicrobial properties. Although HDL is mainly produced by the liver, the intestine is also a source. Han et al. show in mice that intestinal HDL is not routed to the systemic circulation. Rather, in the form of HDL3, it is directly transported to the liver through the hepatic portal vein. There, it sequesters bacterial lipopolysaccharide from the gut that can trigger inflammation and liver damage. In various models of liver injury, loss of enteric HDL exacerbated pathology. By contrast, drugs elevating intestinal HDL improved disease outcomes. HDL3 is enriched in human portal venous blood, suggesting that enteric HDL may be targetable for the treatment of liver disease.
Science, abe6729, this issue p. eabe6729
Structured Abstract
INTRODUCTION
High-density lipoprotein (HDL) participates in cholesterol homeostasis and may also have anti-inflammatory or anti-microbial roles through its interaction with numerous plasma proteins. The liver synthesizes most HDL in the body, but the intestine also produces HDL. However, a role for intestinal HDL distinct from that produced by the liver has not been identified. While remodeling its cargo, HDL particles circulate through tissue spaces, but so far, HDL trafficking within tissues has been scarcely studied.
RATIONALE
We reasoned that understanding HDL-trafficking patterns might bring insight into its roles in health and disease, including whether HDL made by the intestine is functionally redundant with that produced by the liver. Using a knock-in mouse that we previously generated to phototag HDL in any tissue location, we aimed to trace the fate of HDL synthesized by the intestine.
RESULTS
Phototagged HDL derived from small bowel enterocytes was generated most abundantly by the ileum and did not travel into draining lymphatic vessels as enterocyte-derived chylomicrons do. Instead, intestinal HDL rapidly entered the portal vein, the major blood supply to the liver. This finding raised the issue of whether the liver might benefit from intestinal HDL and pointed us to an older concept that HDL might neutralize a key microbial signal that can escape a permeable gut: lipopolysaccharide (LPS) from Gram-negative bacteria. Past studies using multiple models have shown that LPS engagement of its receptor, Toll-like receptor 4 (TLR4), in the liver drives significant liver pathology, including inflammation that progresses to fibrosis. Using biochemical, proteomic, and functional approaches, we observed that the intestine produces a particular subspecies of HDL called HDL3. Unlike another HDL subspecies (HDL2), HDL3 sequestered LPS so efficiently that it could not bind to TLR4+ liver macrophages. In this way, HDL3 produced by the intestine protected the liver from the inflammation and fibrosis observed in a variety of mouse models of liver injury that parallel clinically relevant conditions in humans, including surgical resection of the small bowel, alcohol consumption, or high-fat diets. Administration of an oral drug targeting the transcription factor liver X receptor, the master regulator of genes associated with HDL biogenesis, raised enteric HDL levels and protected the mice from liver pathology. This protection was lost if mice did not express enterically derived HDL, indicating that intestinal HDL was a key target of the drug. Six samples of human portal venous blood with matched systemic venous blood confirmed the enrichment of HDL3.
Mechanistically, LPS-binding protein (LBP) was enriched in HDL3 particles and was required for HDL3 to mask LPS from detection by TLR4. This finding was unexpected because LBP otherwise promotes TLR4 signaling by shuttling LPS to CD14, which then shuttles it to TLR4. Thus, HDL3 interacts with a known component of the TLR4-signaling platform, LBP, to hide LPS from detection. Without binding to TLR4, the HDL3-LBP-LPS complex was not retained in liver. Instead, it exited the liver while the LPS associated with it was inactivated. The enzyme acyloxyacyl hydrolase, which is produced in part by liver macrophages and which deacylates critical fatty acid residues in LPS for TLR4 activation, could still access and act upon HDL3-associated LPS to detoxify it. Low-density lipoprotein bound LPS, but not LBP, and was thus unable to prevent LPS activation of liver macrophages. LBP is in the same family of lipid-binding proteins as phospholipid transfer protein and cholesterol ester transfer protein, which have well-established roles in remodeling the lipid configuration of HDL. Another microbial lipid, lipoteichoic acid from Gram-positive bacteria, is known to bind LBP. We found that it too complexed with HDL3 and suppressed the activation of liver macrophages.
CONCLUSION
The production of HDL by small bowel enterocytes in a form that potently masks LPS comprises a disease tolerance strategy to protect the liver from injury of enteric origin. Enteric HDL may thus be a suitable pharmacologic target for protecting the liver against gut-derived LPS leakage in alcoholic and nonalcoholic settings.
Trafficking and functional properties of enteric HDL.
Enterocytes express ABCA1 to promote HDL biogenesis. The nascent HDL enters portal venous blood bearing LBP, which allows it to hide LPS from recognition by TLR4+ macrophages. Failed recognition prevents macrophage activation. Although its ability to trigger macrophages is suppressed by HDL3, LPS in the HDL3 complex can still be inactivated by acyloxyacyl hydrolase. Figure was drawn with BioRender.
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.
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