An intestine-derived HDL as a novel regulator of the activity of gut-derived LPS: Ushering in a new era of research on the gut-liver axis

Summary

High-density lipoprotein (HDL) plays an important role in cholesterol metabolism and has anti-inflammatory or anti-microbial properties. HDL is synthesized in the liver and small intestine that produce apolipoprotein A1 (apoA1), the core structural protein of HDL. The intestine is one of the two HDL sources, but intestine-derived HDL has been overlooked since the liver produces most systemic HDL. Despite the increasing relevance of the gut-liver axis in health and disease (J Hepatol 2020;72:558-77), neither intestinal HDL’s fate nor function is fully understood.

In a recent article published in Science, Han et al demonstrated that intestinal HDL can reach the liver through the portal vein and protect it from liver injury induced by gut-derived lipopolysaccharide (LPS). The study first examined HDL-trafficking patterns by tracing the fate of HDL synthesized in the intestine and then investigated the role of intestinal HDL. By phototagging HDL in photoactivatable green fluorescent protein apoA1 knock-in mice, Han et al found that phototagged HDL was produced mostly by enterocytes in the ileum. This phototagged HDL did not enter the draining lymphatic circulation, but instead reached the liver through the portal vein, suggesting the role of intestinal HDL in the gut-liver axis. Further, the authors found that the portal vein HDL was mainly in the form of small HDL, called HDL₃; it interacts with LPS in an LPS-binding protein (LBP)-dependent manner, suggesting that portal venous HDL₃ affects LPS activity. Then, the study showed that HDL₃-bound LPS suppressed toll-like receptor 4 (TLR4)-mediated inflammatory responses in Kupffer cells, suggesting that portal HDL₃ sequesters LPS to limit inflammation by preventing LPS binding to Kupffer cells. Han et al further confirmed that inhibiting intestinal HDL production worsens liver inflammation and fibrosis in three murine models of liver injury, including surgical resection of small bowel, alcohol consumption, and high-fat diets. Lastly, the authors tested the therapeutic potential of intestinal HDL by activating liver X receptors (LXRs), the master regulators of HDL biosynthesis. Oral administration of the LXR agonist raised the enteric HDL levels and alleviated liver inflammation and fibrosis. However, the LXR agonist failed to protect the liver from injury in intestinal HDL-deficient mice.

In this study, the authors discovered that the novel function of intestine-derived HDL₃ that protects liver injury from gut-derived LPS, suggesting that HDL₃ can be a pharmacological target for treating liver disease associated with gut leakiness.

Commentary

HDL is commonly referred to as “good cholesterol”. The beneficial effect of HDL has been attributed to its ability to transfer cholesterol from extrahepatic tissues to the liver for metabolism and excretion into bile, a process called reverse cholesterol transport (J Lipid Res 1968;9:155-67; Adv Lipid Res 1973;11:1-65). In addition to regulating cholesterol metabolism, HDL also exhibits anti-oxidative, anti-microbial, and anti-inflammatory properties (Front Cardiovasc Med 2020;7:39). The biogenesis of HDL is complex. HDL, apoA1, and the APT-binding cassette, subfamily A, member 1 (ABCA1) are the core components required to form HDL particles. Liver and small intestine are the two major tissues for apoA1 synthesis (J Biol Chem 1979;254:7316-22). Liver synthesizes the majority of HDL, but intestine can also produce HDL. However, it was unclear why HDL is synthesized in the intestine rather than solely in the liver. The study reported by Han et al demonstrated that intestine produces a particular HDL subspecies HDL₃, and HDL₃ is delivered to the liver through the portal vein. Although a previous report showed that intestinal epithelial cells produce HDL particles (J Lipid Res 1973;14:215-23), this study, for the first time, provided evidence that enterically-derived HDL enters the portal vein to reach the liver without passing through lymph vessels. This finding suggests the new role of intestinal HDL in the gut-liver axis.

The portal vein collects venous drainage from intestine, delivering nutrients and metabolites of intestinal host and microbiome origin to the liver as its major blood supply (J Hepatol 2020;72:558-77). Through this route, gut-derived factors, including harmful and toxic substances, like bacterial LPS may also be delivered to the liver and promote liver inflammation and fibrosis (Nature 2019;575:505-11). Indeed, intestine-derived LPS triggers proinflammatory and profibrotic pathways in a TLR4-dependent manner (Gastroenterology 2006;130:1886-900; Hepatology 2008;48:1224-31). In this study, Han et al demonstrated that the portal HDL₃ forms the complex with LPS through LBP; this complex can mask the LPS activity to prevent LPS binding to Kupffer cells, inhibiting the induction of proinflammatory and profibrotic genes. Although the ability of HDL to neutralize LPS was reported previously (Proc Natl Acad Sci USA 1993;90:12040-4; J Exp Med 1995;181:1743-54), the authors discovered that the intestine-derived HDL₃ can capture LPS locally before it accesses to the liver. Since liver can be constantly exposed to LPS due to the direct anatomical connection to the gut through the portal vein, intestinal HDL might serve as the primary defense mechanism against intestine-derived endotoxin to the liver. Besides, in vivo data strongly support this concept by showing that inhibition of enterically produced HDL exacerbates liver inflammation and fibrosis in three different murine models of liver injury involving metabolic, alcoholic, and surgical resection of intestine. With the increasing relevance of the gut-liver axis in health and disease, this study provides a novel insight into pathogenesis and therapeutic strategies of liver disease associated with the gut leakiness.

Another significant finding by Han et al is that oral administration of LXR agonists proved effective in protecting the liver by increasing enteric HDL₃ levels. HDL had received huge interest from many researchers and clinicians, originally because of its role in cardiovascular disease. Despite strong evidence showing an inverse association between HDL cholesterol and the risk of cardiovascular disease, multiple clinical trials testing drugs that raise systemic level of HDL-cholesterol, such as cholesteryl ester transfer protein (CETP) inhibitors, for improving cardiovascular disease were not successful (N Engl J Med 2007;357:2109-22; N Engl J Med 2012;367:2089-99; N Engl J Med 2017;376:1933-42; N Engl J Med 2017;377:1217-27). Also, the clinical availability of LXR agonists is still challenging because systemic LXR activation could contribute to increased triglyceride synthesis, hypertriglyceridemia, and hepatic steatosis (Genes Dev 2000;14:2831-8; J Biol Chem 2002;277:34182-90). Nevertheless, the findings by Han et al and others (Circ Res 2006;99:672-4; Cell Metab 2010;12:187-93) demonstrated that oral administration of low-dose LXR agonist only elevates a specific type of HDL specifically in the intestine. This suggests that intestinal HDL may be an attractive target for pharmacological intervention and that enteric HDL-raising LXR agonists or other approaches to elevate intestinal HDL remain promising in the treatment of liver disease and also cardiovascular disease.

Several questions remain to be answered. First, it remains elusive why most portal venous HDL-cholesterol is derived from intestine. Although liver is the predominant source of plasma HDL, intestinal HDL accounts for most HDL in the portal blood. Besides the intestine, the pancreas and spleen also drain the venous blood into the portal vein. Intestine-derived and systemic blood could be mixing and drain into the portal vein. However, the authors hardly detected systemic HDL in the portal vein. Han et al proposed the possible extravasation of systemic HDL near or within the intestine. After extravasation, large-sized HDL₂ that has entered or formed in the intestinal interstitium from the periphery may be too large to enter the fenestrated blood vessels that drain into the portal vein such that only enterically produced HDL₃ can gain efficient access. Another question is how LPS and LBP interact with HDL₃ to reduce the bioactivity of LPS. LPS binds and activates TLR4 with the support of LBP and CD14 (Immunity 2017;46:38-50; BMB Rep 2017;50:55-7). According to this study, LBP conversely mediates the neutralizing effect of HDL₃ for the sequestration of LPS. This finding provides a new angle on the action of LBP. Future studies are needed to understand the underlying mechanism.

The present study revealed the fate and role of HDL synthesized by the intestine and provided translational potential by suggesting HDL₃ as an attractive pharmacological target in the treatment of liver disease mediated by increased intestinal permeability. The knowledge from this study can provide significant insight into the novel understanding of the gut-liver axis, which is associated with a variety of liver diseases, including non-alcoholic fatty liver disease, alcohol-associated liver disease, liver fibrosis, primary and metastatic liver cancers, and also cirrhosis-mediated conditions, such as spontaneous bacterial peritonitis, hepatic encephalopathy, and hepato-renal syndrome.