[ad_1]
Intestinal HDL is hepatoprotective
High density lipoproteins (HDL) are important for cholesterol metabolism and may have anti-inflammatory and antimicrobial properties. Although HDL is primarily produced by the liver, the intestine is also a source. Han et al. show in mice that intestinal HDL are not transported to the systemic circulation. On the contrary, in the form of HDL3, it is transported directly to the liver through the hepatic portal vein. There, it sequesters bacterial lipopolysaccharide from the intestine which can trigger inflammation and liver damage. In various models of liver injury, loss of enteric HDL exacerbated the pathology. In contrast, drugs that elevate intestinal HDL improved disease outcomes. HDL3 is enriched in human portal venous blood, suggesting that enteric HDL may be targeted for the treatment of liver disease.
Science, abe6729, this issue p. eabe6729
Structured summary
INTRODUCTION
High density lipoproteins (HDL) participate in cholesterol homeostasis and may also have anti-inflammatory or antimicrobial roles through its interaction with many plasma proteins. The liver synthesizes most of the HDL in the body, but the intestine also produces HDL. However, a role of intestinal HDL distinct from that produced by the liver has not been identified. During the remodeling of its cargo, HDL particles circulate through tissue spaces, but so far HDL trafficking in tissues has hardly been studied.
REASONING
We felt that understanding HDL trafficking patterns could provide insight into its roles in health and disease, especially if HDL made by the gut is functionally redundant with that produced by the liver. Using a knock-in mouse that we previously generated to photolabel HDL in any tissue location, we sought to trace the fate of HDL synthesized by the gut.
RESULTS
Photolabeled HDL derived from enterocytes in the small intestine was generated most abundantly by the ileum and did not travel through draining lymphatics as do enterocyte-derived chylomicrons. Instead, intestinal HDL quickly entered the portal vein, the liver’s main blood supply. This discovery raised the question of whether the liver could benefit from intestinal HDL and pointed to an older concept that HDL could neutralize a key microbial signal that can escape from a leaky gut: lipopolysaccharide (LPS). Gram-negative bacteria. Previous studies using multiple models have shown that engagement of LPS from its receptor, the Toll-like receptor 4 (TLR4), in the liver results in significant liver disease, including inflammation that progresses to fibrosis. Using biochemical, proteomic and functional approaches, we observed that the gut produces a particular subspecies of HDL called HDL3. Unlike another HDL subspecies (HDL2), HDL3 sequestered LPS so effectively that it could not bind to TLR4+ macrophages of the liver. In this way, HDL3 produced by the intestine protected the liver from inflammation and fibrosis seen in a variety of mouse models of liver damage that correspond to clinically relevant conditions in humans, including surgical resection of the small intestine, alcohol consumption or high fat diets. Administration of an oral drug targeting the liver transcription factor X receptor, the main regulator of genes associated with HDL biogenesis, increased enteric HDL levels and protected mice from liver disease. This protection was lost if the mice did not express enteric HDL, indicating that intestinal HDL was a key drug target. Six human portal venous blood samples with matched systemic venous blood confirmed HDL enrichment3.
Mechanically, the LPS binding protein (LBP) was enriched for HDL3 particles and was required for HDL3 to mask the LPS from TLR4 detection. This discovery was unexpected because LBP further promotes TLR4 signaling by shuttling LPS to CD14, which then transports 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, HDL3-The LBP-LPS complex was not retained in the liver. Instead, it exited the liver while the LPS associated with it was inactivated. The enzyme acyloxyacyl hydrolase, which is produced in part by hepatic macrophages and deacylates critical fatty acid residues in LPS for TLR4 activation, could still access and act on HDL3-associated with LPS to detoxify it. Low density lipoproteins bound to LPS, but not to LBP, and therefore were unable to prevent LPS activation of hepatic macrophages. LBP belongs to the same family of lipid binding proteins as phospholipid transfer protein and cholesterol ester transfer protein, which have a well-established role in remodeling the lipid configuration of HDL. Another microbial lipid, lipoteichoic acid from Gram-positive bacteria, is known to bind to LBP. We found that he was too self-conscious about HDL3 and suppressed the activation of hepatic macrophages.
CONCLUSION
The production of HDL by enterocytes in the small intestine in a form that powerfully masks LPS involves a disease tolerance strategy to protect the liver from damage of enteric origin. Enteric HDL may therefore be an appropriate pharmacological target for protecting the liver against LPS leakage of intestinal origin in alcoholic and non-alcoholic environments.
Enterocytes express ABCA1 to promote HDL biogenesis. Nascent HDL enters portal venous blood carrying LBP, allowing it to mask LPS from recognition by TLR4+ macrophages. Failure of recognition prevents activation of macrophages. Although its ability to trigger macrophages is suppressed by HDL3, LPS in HDL3 complex can still be inactivated by acyloxyacyl hydrolase. The figure was drawn with BioRender.
Abstract
High density lipoprotein (HDL) biogenesis 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 HDL derived from the intestine crosses the portal vein into HDL3 subspecies form, in complex with lipopolysaccharide binding protein (LPS) (LBP). HDL3, but not HDL2 or low density lipoproteins, prevented LPS binding and inflammatory activation of hepatic macrophages and instead supported extracellular inactivation of LPS. In mouse models involving surgical, dietary, or alcoholic intestinal insult, loss of gut-derived HDL worsened liver damage, while outcomes were improved by treatments that increased and depended on increased intestinal HDL. Thus, the protection of the liver against lesions in response to LPS of intestinal origin is a major function of HDL synthesized by the intestinal route.
[ad_2]
Source link