Bile Acids in Alcohol-Associated Liver Disease: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Huiping Zhou.

Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead to the development of hepatocellular carcinoma (HCC). ALD continues to be a significant health burden and is now the main cause of liver transplantations in the United States. ALD leads to biological, microbial, physical, metabolic, and inflammatory changes in patients that vary depending on disease severity. ALD deaths have been increasing in recent years and are projected to continue to increase. Current treatment centers focus on abstinence and symptom management, with little in the way of resolving disease progression. Due to the metabolic disruption and gut dysbiosis in ALD, bile acid (BA) signaling and metabolism are also notably affected and play a prominent role in disease progression in ALD, as well as other liver disease states, such as non-alcoholic fatty liver disease (NAFLD).

  • alcohol-associated liver disease
  • bile acids
  • ethanol

1. Introduction

The use of alcohol is estimated to date back to 8000 BC, with the earliest proof in the form of chemical analysis dating back to 7000 to 6600 BC [1]. Alcohol has been used as a medicine, ointment, and cleaning agent and has been indulged in over the centuries. Alcohol-associated liver disease (ALD), also previously known as alcoholic liver disease, is a clinical illness caused by excessive and/or chronic alcohol use that has significant health and economic impacts. ALD is associated with a marked increase in lipid droplets in hepatocytes. It becomes classified as alcoholic fatty liver or steatosis once greater than 5% of hepatocytes develop this fatty phenotype [2]. These lipid droplet accumulations can be classified as macrovesicular, large lipid droplets that displace the nucleus and organelles or microvesicular, smaller lipid droplets that do not displace the nucleus, which tend to be more common in ALD [2]. The amount of fat in the liver can be measured by a specialized ultrasound device called a FirboScan [3]. However, alcoholic steatosis is rarely diagnosed, as it is largely asymptomatic. The lack of early detection often allows for further progression along the ALD spectrum that encompasses simple steatosis, alcoholic hepatitis (AH), alcoholic liver fibrosis, and alcoholic cirrhosis (AC) and can ultimately develop into hepatocellular carcinoma (HCC). The current standard treatment for ALD is (and has been for decades) abstinence, as well as dietary and lifestyle changes prior to cirrhosis and liver transplantation for end-stage treatment [4,5,6][4][5][6]. ALD is closely associated with metabolic, physiologic, and inflammatory changes; gut dysbiosis; and altered bile acid (BA) synthesis, recycling, and signaling [6,7,8,9,10,11][6][7][8][9][10][11]. Lipid and lipoprotein profiles have been shown to be significantly different in patients with AH vs. heavy drinkers and could be used in prognosis [12]. AH patients have worse liver function compared to never-decompensated ALD, with AH being associated with bilirubinostatsis, severe fibrosis, ductular reaction, and aberrant gene expression [13]. Gut dysbiosis leads to increased inflammation, as well as altered BA signaling, due to changes in intestinal microbial modifications of BAs and has been associated with ALD, non-alcoholic fatty liver disease (NAFLD), and autoimmune liver disease [14]. More recently, not only has bacterially associated gut dysbiosis been important, but fungal changes in the intestinal microbiome have shown associations with ALD as well [15]. BAs are not only important in absorption of cholesterol and lipids but also act as critical signaling molecules that regulate lipid and glucose metabolism, as well as immune response. Impaired BA homeostasis has been linked with ALD and cirrhosis [16,17,18,19,20][16][17][18][19][20].

2. Bile Acid Enterohepatic Circulation

BAs are amphipathic steroid molecules derived from a multistep enzymatic pathway. De novo BA synthesis begins with cholesterol in the liver. After BAs are formed in the hepatocytes of the liver, they are transported into the bile canaliculi by the efflux transporter bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2). Once in the bile canaliculi, BAs then flow to and are stored in the gallbladder. Upon ingestion of fats and proteins, cholecystokinin (CCK) is released from endocrine cells in the small intestine. CCK then signals the smooth muscle cells of the muscularis layer of the gallbladder to contract and the sphincter of Oddi to relax, releasing bile into the cystic duct. Bile enters the common bile duct from the cystic duct and flows into the ampulla of Vater before entering the duodenum. Most of the BAs are reabsorbed in the intestines via the hepatic portal vein to end up in the liver again and start the cycle anew. This cycle is referred to as enterohepatic circulation. A proportion of 95% of BAs are absorbed in the intestines, with the majority being absorbed in the terminal ileum by active transport via the apical sodium-dependent bile transporter. The BAs are then transported across the enterocyte into the sinusoidal membrane, where epithelial cells’ organic sulfate transporter-α and -β (OST-α and -β) transport the BAs into portal blood. Once BAs in the portal vein reach the liver, hepatocytes uptake the BAs via Na+-taurocholate cotransporting polypeptides (NTCPs) and organic anion transporting polypeptides (OATPs) on the basolateral membrane [59,60,61][21][22][23]. OATP1B1 and OATP1B3 have been shown to preferentially transport conjugated BAs over unconjugated BAs [62][24]. The BAs left in the intestinal lumen are altered by gut bacteria. Bacterial modifications include deconjugation, 7-dehydroxylation, amidation, oxidation-reduction, esterification, and desulfation [63,64,65][25][26][27]. Humans have a total bile production of ~600 mL and a BA pool size of 4 to 6 g, releasing approximately 12 to 30 g into the intestines daily; these BAs recirculate an average of three to five times [66,67,68,69][28][29][30][31]. BAs can be categorized as primary bile acids or secondary bile acids, each of which can be conjugated or unconjugated. In humans, the liver produces two primary bile acids—cholic acid (CA) and chenodeoxycholic acid (CDCA)—whereas rodents produce CA, CDCA, and α- and β-muricholic acids (α- and β-MCA). Human secondary bile acids consist of deoxycholic acid (DCA) and lithocholic acid (LCA), whereas mouse secondary bile acids consist of murideoxycholic acid (MDCA), hyodeoxycholic acid (HDCA), and ω-Muricholic acid (ω-MCA) [69][31]. Both humans and mice can have ursodeoxycholic acid (UDCA). BAs can be conjugated by the addition of taurine or glycine. Murine BAs are mostly taurine-conjugated, whereas human BAs are mainly glycine-conjugated [70][32]. Another distinguishing difference is that the murine BA pool is more hydrophilic than the human BA pool [71][33].

3. Bile Acid Metabolism

The primary bile acids are produced from cholesterol via two well-characterized pathways: the classical (neutral) pathway and the alternative (acidic) pathway [72][34]. The classical pathway accounts for ~90% of BA formation, with the alternative pathway making up the final 10%. This catabolic process requires more than a dozen enzymes to modify the cholesterol steroid core. Human BAs have 24 carbon atoms, with a steroid core that consists of three six-member rings and a five-member ring. The rate-limiting steps for both the classical and alternative pathways are the initial enzymes for each of them: cholesterol 7α-hydroxylase (CYP7A1) and cholesterol 27α-hydroxylase (CYP27A1), respectively. CYP7A1 hydroxylates at the C7 position of cholesterol to form 7α-hydroxycholesterol, whereas CYP27A1 hydroxylates cholesterol at C27 to form 27-hydroxycholesterol. In the classical pathway, 7α-hydroxycholesterol is then converted to 7α-hydroxy-4-cholesten-3-one (C4) by 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) [73][35]. A multi-enzymatic process that results in a double-bond reduction, further hydroxylation, and side-chain cleavage converts C4 to CDCA via aldo-keto reductase 1D1 (AKR1D1), 3α-hydroxysteroid dehydrogenase (3αHSD), and CYP27A1 [73][35]. Microsomal sterol 12α-hydroxylase (CYP8B1) interacts with C4 to form 7α,12α-hydroxy-4-cholesten-3-one and regulates the CA-to-CDCA ratio [74][36]. 7α,12α-hydroxy-4-cholesten-3-one is then altered by other subsequent enzymes to form CA. In the alternative pathway, CYP27A1, located in the inner mitochondrial membrane, is the first step of the enzymatic process, followed by oxysterol 7α-hydroxylase (CYP7B1). A recent study showed that CYP7B1 is responsible for controlling the levels of intracellular regulatory oxysterols produced by the alternative pathway [75][37]. The alternative pathway is believed to mainly produce CDCA. Following further subsequent enzymatic alterations by AKR1D1 and 3αHSD, as well as others, CDCA is formed [73][35]. Bile acid–CoA synthase (BACS) and bile acid–CoA: amino acid N-acetyltransferase (BAAT) then add glycine or taurine to CA and CDCA to produce the conjugated bile acids glycocholic acid (GCA), taurocholic acid (TCA), glycochenodeoxycholic acid, and taurochenodeoxycholic acid (TCDCA). In mice, CDCA and UDCA are converted to α-MCA and β-MCA by cytochrome p450 2C70 (CYP2C70) and are then conjugated with taurine or glycine [71,76][33][38]. The bile acids then undergo enterohepatic circulation as previously described. In the intestine, BAs can be further modified by a variety of bacteria to form secondary BAs. One of the major bacterial alterations of BAs is the deconjugation of conjugated BAs by bile salt hydrolase (BSH) enzymes. BSH protein sequences have been identified in 591 intestinal bacteria strains within 117 genera of human microbiota and reclassified into 8 phylotypes [77][39]. Lactobacillus BSH has been shown to have the highest enzyme activity, whereas BSH phylotypes BSH-T5 and -T6 are mainly from Bacteroides, with a high percentage of paralogs that exhibit different enzyme activity [77][39]. Another important microbial modification is 7α-dehydroxylation, which converts CA and CDCA to DCA and LCA, respectively, as well as 7β-dehydroxylation, which converts UDCA to LCA [64][26]. BAs can also be modified by dehydrogenation, oxidation, epimerization; more recently, gut microbiota have been shown to conjugate amino acids to bile acids, termed microbially conjugated bile acids [78,79][40][41]. BA synthesis, reabsorption, metabolism, and the effects that BAs mediate are heavily regulated by and carried out through their interactions with receptors.

4. Bile Acid Signaling

Maintaining BA homeostasis is an important physiological process that focuses on regulating synthesis, absorption, and excretion. This regulation is controlled by several specific nuclear and surface receptors, transporters, and their subsequent signaling cascades and secondary signaling molecules. BAs can interact with several receptors, leading to the activation of a plethora of secondary signaling molecules that lead to a variety of metabolic and homeostatic changes. BA nuclear receptors include the farnesoid X receptor (FXR) [80][42], the pregnane x receptor (PXR) [81[43][44],82], and the vitamin D receptor (VDR) [83][45]. The FXR has two members in mammals: FXRα and FXRβ [84][46]. FXRα has four isoforms, FXRα1-α4, whereas FXRβ encodes functional receptors in other species but is a pseudogene in humans and primates [85,86,87][47][48][49]. The FXRα isoforms exhibit locational differences in expression, with FXRα1 and FXRα2 being moderately expressed in the ileum and adrenal glands and FXRα3 and FXRα4 being highly expressed in the ileum and moderately expressed in the kidneys [87][49]. FXR binds to CDCA, LCA, DCA, and CA [80,88,89][42][50][51]. The FXR has been shown to regulate the metabolism of and is the major coordinator of bile acids, carbohydrates, lipids, and absorption of dietary fats and vitamins and plays an important role in the anti-inflammatory response and inhibition of hepatocarcinogenesis [84,90][46][52]. Upon activation, FXR forms a heterodimer with retinoid X receptor α (RXRα), the allosteric signal transduction of which was recently investigated, showing changes in affinity and conformational changes in helix 11 of the FXR[91][53]. Activation and heterodimerization lead to the expression of small heterodimer partner (SHP), BACS, and BAAT and lead to transcriptional repression of CYP7A1 and liver homolog 1 [92,93,94][54][55][56]. SHP leads to repression of NTCP, reducing BA uptake of hepatocytes and CYP7A1, reducing BA synthesis [92,95][54][57]. FXR also leads to the expression of bile salt export pump (BSEP), OST-α and -β, multidrug resistance protein 2 (MRP2), and multidrug resistance protein 3 (MDR3) [96,97,98,99][58][59][60][61]. SHP mediates liver X receptor (LXR) anti-inflammatory effects by SUMOylation of LXR, with knockdown of SHP abrogating LXR SUMOylation, preventing its anti-inflammatory effects [100][62]. BSEP, MRP2, and MDR3 all transport their targets into the bile canaliculus and are critical in the healthy production and composition of bile. PXR is activated by 3-keto-LCA and LCA [82,89][44][51]. PXR activation is also associated with RXRα heterodimerization and leads to increased drug metabolism, drug transport, and lipogenesis while decreasing gluconeogenesis, glycogenolysis, β-oxidation/ketogenesis, and BA synthesis [89,101][51][63]. PXR has been shown to regulate liver size in mice by treatment of PXR-selective activators, leading to liver enlargement and induction of regenerative hybrid hepatocyte reprogramming via a Yes-associated protein mechanism [102][64]. VDR is activated by secondary bile acids, such as LCA and LCA derivatives, including LCA acetate and LCA propionate [83,103,104][45][65][66]. Like other BA nuclear receptors, upon activation, VDR is associated with RXR and then binds to specific DNA elements to affect various proteins at the transcriptional level [83][45]. VDR is highly regulated in the intestinal tract and is also expressed in the kidney [89][51]. VDR as a BA receptor may play a protective role. In intestinal cells, VDR induces expression of CYP3A, which metabolizes toxic LCA and can help prevent degradation of the intestinal barrier and entrance of LCA into enterohepatic circulation, leading to LCA hepatoxicity [83,105][45][67]. BA G protein-coupled receptors include Takeda G protein-coupled receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and muscarinic acetylcholine receptor M3 (M3R). TGR5, also called the G protein-coupled bile receptor 1 (GPBAR1), which was the first BA non-nuclear receptor discovered, was also found to mediate a range of physiological functions, such as maintenance of metabolic homeostasis and insulin sensitivity [106,107][68][69]. TGR5 is mainly activated by unconjugated and secondary BAs [106][68]. TGR5 can associate with either stimulatory or inhibitory G alpha proteins (Gαs or Gαi), depending on the cell type [89][51]. In most cells, TGR5 couples with Gαs and BA binding and leads to receptor internalization, activation of extracellular signal-related kinase, mitogen-activated protein kinase, and activation of adenylate cyclase, as well as an increase in cyclic AMP [108][70]. In cholangiocytes, TGR5 can couple with either Gαs or Gαi, depending on subcellular localization [109][71].

5. Bile Acids in Disease

BA accumulation has been associated with liver injury, chronic liver disease, inflammation, and tumorigenesis[20,115,116][20][72][73]. High levels of secondary bile acids in feces and blood have been associated with cholesterol gallstones and colon cancer [117][74]. An observational study revealed that BAs are significantly increased in liver cirrhosis, with the reseauthorchers suggesting using total and individual BAs, especially primary CBAs, as non-invasive markers for diagnosis of liver cirrhosis, with potential for use as indicators for HCC [56][75]. In a recent study looking at BAs and cancer cachexia, mouse total BA levels significantly increased, but BA synthesis enzyme expressions were inhibited [118][76]. Changes in BA metabolism and an increase in BA conjugation in clinical patients were also observed [118][76]. CBA TCA has been shown to significantly promote cell proliferation, migration, invasion, transformation, and cancer stem cell expansion in esophageal adenocarcinoma cells via S1PR2 [119][77]. DCA dietary supplementation in a preclinical non-alcoholic steatohepatitis mouse model restored BA concentrations in portal blood; increased TGR5 and FXR signaling; ameliorated metabolic dysbiosis; and protected against steatosis, ballooning, and macrophage infiltration [120][78]. However, an abnormally high level of microbially modified DCA has been associated with gut dysbiosis, disruption of mucosal physical and functional barriers, and intestinal carcinogenesis [121,122][79][80]. Downregulation of FXR, the major BA nuclear receptor, alters the gut microbiome by facilitating Bacteroides fragilis colonization, which leads to the promotion of colorectal tumorigenesis [123][81]. Inhibition of FXR and BA metabolism modulation by trimethylamine N-oxide exacerbates steatosis in non-alcoholic fatty liver disease [124][82]. The FXR has also been investigated as a therapeutic target for cardiometabolic diseases [125][83]. Conjugated BAs can interact with S1PR2 and promote neuroinflammation during hepatic encephalopathy in mice, suggesting that reduction in BAs or S1PR2 signaling is a potential therapeutic strategy for hepatic encephalopathy [126][84]. BA activation of M3R has been shown to induce proliferation in human colon cancer cell lines via epidermal growth factor receptors, and M3R activation stimulates colon cancer cell invasion through MAPK-ERK1/2 and induction of matrix metalloproteinase-1 expression [127,128][85][86].

6. Bile Acids in ALD

Alcohol alters many metabolic pathways, including BA and cholesterol metabolism, and causes inflammation and injury to multiple organ systems. Conversely, maintaining metabolic homeostasis is protective against the deleterious effects of alcohol. The authors of one murine studyesearchers observed that ethanol increased BA levels, BA synthesis genes (CYP7A1, CYP27A1, CYP8B1, and BAAT), and BA transporters but downregulation in BA transporter NTCP in the liver and nuclear receptor FXR in the ileum [129][87]. However, in humans, researchers observed that total and conjugated BAs are significantly increased in patients with AH, but de novo synthesis is suppressed based on a decrease in CYP7A1 gene expression and C4 serum levels [130][88]. ThFis same study found that fibroblast growth factor 19 (FGF19) correlated with total and conjugated Bas, and FGF19 has significant associations with bilirubin and gamma-glutamyl transferase [130][88]. Plasma TCDCA and tauroursodeoxycholic acid levels have been observed to be directly related to disease severity in ALD, whereas fecal ursodeoxycholic acid was inversely related [116][73]. CYP7A1-deficient mice (the rate-limiting step in BA synthesis) have greater hepatic inflammation and injury from alcohol than wild-type mice, and hepatic injury is ameliorated in CYP7A1 transgenic mice, suggesting CYP7A1 and BA synthesis play a protective role in ALD [131][89]. An altered BA glycine-to-taurine ratio has been associated with stage-specific liver disease patterns and may be used as new biomarkers for monitoring disease progression [132][90]. PPARα has been found to be significantly reduced in the liver of severely alcoholic hepatitis patients [34][91]. The modulation of fatty acid and bile acid metabolism by PPARα showed protective effects against ALD via investigation of comparative gene expression of wild-type and PPARα-null mice [133][92]. As mentioned previously, PPARα also showed protective effects against ethanol metabolism toxicity by shunting it from the ROS-generating CYP2E1 pathway to the ROS-scavenging catalase pathway [34][91]. PPARα-null mice exhibited an increase in alcohol-associated accumulation of triglycerides, hepatic cholic acid and derivatives, and induction of fibrogenesis genes compared to wild-type mice [133][92]. The observed disparities contributed to PPARα’s mitochondrially protective effects via modulation of three mitochondrial metabolic pathways [133][92]. In preclinical studies, a PPARα agonist, seladelpar, was shown to reduce ethanol-induced liver disease through gut barrier restoration and bile acid homeostasis [134][93]. Coupling the preclinical protective effects of PPARα and previously observed results indicating that bile acids induce human PPARα via FXR activation [135][94] suggests that BAs play an important role in the management of ALD progression. PPARα has also been shown to regulate fibrate-mediated suppression of bile acid synthesis through downregulation of cholesterol 7α-hydroxylase and sterol 27-hydroxylase [136][95]. Mice deficient in BA receptor TGR5 had worse alcohol-associated injury than wild-type mice, with an increase in liver macrophage recruitment, altered bile acid profile, and gut microbiota dysbiosis that, when transplanted to WT mice, led to exacerbation of alcohol-induced inflammation [10]. Alcohol consumption induces a change in the gut microbiota, which leads to an increase in bacteria with choloylglycine hydrolase, a BSH, and was coupled with a lower secretion of fibroblast growth factor 15 [137][96]. Although deficiency or inhibition of FXR has been shown to alleviate obesity in NAFLD mice [138[97][98],139], in ALD, it has been shown to cause more damage, and FXR agonists improve ALD [140,141][99][100]. In mice who were either binge-fed or chronically given ethanol, treatment with a TGR5 or FXR agonist ameliorated liver inflammation, steatosis, and injury, which was associated with a reduction in the IL-1β pro-inflammatory cytokine [142][101]. This supports previous research suggesting that TGR5 activation in Kupffer cells leads to a decrease in the pro-inflammatory cytokines IL-1β and tumor necrosis factor-α [143][102]. Another beneficial effect of TGR5 and FXR agonism is the regulation of NLRP3 inflammasome through protein kinase A activation and ubiquitination of NLRP3 [142][101].

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