The Role of Acyloxyacyl Hydrolase in Preventing Liver Disease Linked to Gut Bacteria
The connection between the intestine and liver is facilitated by the portal vein, which plays a critical role in transporting molecules derived from gut commensals, including lipopolysaccharides (LPS) from Gram-negative bacteria, directly to the liver. This mechanism has been extensively studied, and research indicates that gut-derived LPS is a significant contributor to hepatic inflammation, which can exacerbate metabolic dysfunction-associated steatotic liver disease (MASLD). This is particularly evident in cases where dysbiosis, or imbalance in gut microbiota, and intestinal barrier dysfunction occur (Albillos et al., 2020; Leung et al., 2016; An et al., 2022; Aron-Wisnewsky et al., 2020a; Aron-Wisnewsky et al., 2020b).
The pathogenesis of MASLD can be conceptualized in two hits. The first hit is lipid accumulation within hepatocytes, while the second hit is thought to originate from the gut-derived LPS, which primarily induces inflammation (An et al., 2022). However, recent studies have pointed out that the potential direct influence of LPS on hepatocyte lipid metabolism has not been thoroughly examined. For instance, prior research shows that when Aoah+/+ and Aoah-/- mice were co-housed for three weeks, both displayed similar microbiota profiles (Qian et al., 2018). Nevertheless, the Aoah-/- mice exhibited significantly higher levels of LPS in their feces and livers compared to their Aoah+/+ counterparts.
In our latest study, we observed that Aoah-/- mice experienced greater hepatic fat accumulation than Aoah+/+ mice, regardless of whether they were fed a normal chow (NC) diet or a high-fat diet (HFD). Furthermore, the livers of Aoah-/- mice showed increased expression of inflammation-inducing and pro-fibrosis genes and demonstrated more significant liver damage when subjected to an HFD. Notably, even before these mice developed MASLD, their livers displayed significantly elevated levels of nuclear SREBP1 (nSREBP1) and related target genes, suggesting that the process of liver damage began at a much earlier stage.
According to Figure 7 in our findings, Acyloxyacyl hydrolase (AOAH) serves a pivotal role in preventing MASLD by inactivating gut-derived LPS. In the case of Aoah+/+ mice, LPS is deacylated by AOAH, both in the intestine and portal venous blood. However, in Aoah-/- mice, the intact LPS can stimulate fat accumulation and inflammation in the liver, as it is not adequately neutralized. This stimulation leads to increased nSREBP1 levels that enhance fatty acid biosynthesis and promotes the expression of genes responsible for fatty acid uptake while simultaneously inhibiting those related to fatty acid oxidation.
Moreover, the liver is crucial for converting carbohydrates into lipids, with SREBP1c being the predominant isoform responsible for fatty acid synthesis. Research has shown that the mRNA of SREBP1c is significantly elevated in the livers of MASLD patients, suggesting that its chronic activation plays a role in the progression of the disease. Intriguingly, we found that even in young Aoah-/- mice, levels of nSREBP1 were markedly elevated prior to any observable MASLD development, indicating a potential early warning sign of metabolic dysfunction.
Our data indicate that LPS exposure not only increases hepatic LPS levels but also induces the activation of nSREBP1 and its target genes in Aoah+/+ mice, suggesting that gut-derived LPS significantly influences liver metabolism. Specifically, the absence of AOAH leads to heightened SREBP1 activity and, consequently, more pronounced lipogenesis in the liver, worsening MASLD severity.
Furthermore, we noted an increase in AKT-mTOR-S6K activity within the livers of Aoah-/- mice, which may further facilitate the translocation and processing of SREBP1. In isolated primary hepatocytes treated with LPS in vitro, we observed that the upregulation of nSREBP1 was induced via an mTOR-dependent mechanism, hinting at a direct stimulation of hepatocytes by LPS that contributes to lipid accumulation.
Interestingly, while fatty acid biosynthesis gene expression was heightened, the expression of certain fatty acid oxidation-related genes decreased in the livers of young Aoah-/- mice. The CD36 protein, crucial for fatty acid uptake, was also found to increase, further promoting lipid accumulation via complex interactions with regulatory proteins.
In addition to the effects of LPS, AOAH is known to deactivate oxidized phospholipids and lysophospholipidsmolecules that contribute to inflammation and are associated with MASLD progression. By inactivating these harmful substances, AOAH might significantly reduce hepatic fat accumulation and thus offer a potential preventive strategy against MASLD. Increasing the abundance of AOAH could represent a promising approach to combat this prevalent condition.
