Aberrant Brain Bile Acid Signaling and Cholesterol Accumulation: A New Look at Mechanisms in Hepatic Encephalopathy

The article by McMillin et al¹ in the current issue of Cellular and Molecular Gastroenterology and Hepatology documents increased cholesterol accumulation in cerebral cortical neurons of mice treated with the liver toxin azoxymethane (AOM) that was associated with decreased bile acid synthesis, implicating the involvement of brain cholesterol in the pathogenesis of acute hepatic encephalopathy (acute HE).

HE is a major neurologic disorder associated with severe liver disease that presents in acute and chronic forms. HE resulting from acute liver failure occurs after massive liver necrosis, viral hepatitis, acetaminophen toxicity, or exposure to various hepatotoxins. However, the precise mechanism underlying the neurotoxicity of HE still remains unclear. Although the dominant view has been that gut-derived nitrogenous toxins are not extracted by the diseased liver and thereby enter the brain (eg, ammonia) where it exerts deleterious effects, McMillin et al¹ explored a crucial signaling pathway (bile acid signaling and associated defective cholesterol metabolism in brain) that may be involved in pathogenesis of acute HE.

The brain is the most cholesterol-rich organ in the body. The majority (70%–80%) of cholesterol in the adult brain is found in myelin sheaths and in the plasma membranes of astrocytes and neurons. In addition to an essential structural component for cellular membrane and myelin, cholesterol is also a vital precursor of steroid hormones and bile acid synthesis. Such synthesis has been shown to be present in the brain, and is the predominant method by which the brain regulates cholesterol homeostasis. However, currently little is known about the role of bile acid signaling in acute HE.

McMillin et al¹ showed that total and free cholesterol levels, but not esterified cholesterol levels, were increased significantly with the onset of neurologic complications in AOM-treated mice. The investigators showed that such cholesterol accumulation was associated with a decreased bile acid synthesis pathway, which is catalyzed by a cytochrome p450 46A1, through the farnesoid X receptor–mediated mechanisms.

The investigators further documented that treatment of mice with 2-hydroxypropyl-β-cyclodextrin (2-HβC), a modified cyclodextrin, which is well known to change the physicochemical properties of lipophilic compounds, diminished the AOM-induced cholesterol accumulation in the brain. A unique aspect of this study was an investigation into whether the cholesterol build-up in the brain plays any role in the neurologic deficits associated with acute liver failure. McMillin et al¹ documented that treatment of mice with 2-HβC before AOM injection significantly delayed the neurologic decline, and increased the time taken to reach hepatic coma, suggesting that the neuroprotective actions of 2-HβC likely were due to the prevention of cholesterol build-up in brain. In addition, the investigators examined neuromuscular complications in HE that may be pertinent to the role of cholesterol in this condition. They found that AOM-treated mice showed an increased degree of external rotation of both the forelimbs and hind limbs, which commonly occurs in ataxia, and that treatment with 2-HβC reduced this effect.

Although these findings provide valuable information regarding the role of cholesterol and bile acid synthesis in the pathogenesis of HE, further investigations related to the factors/mechanisms involved in cholesterol metabolism and bile acid synthesis may provide a better understanding of the molecular events involved in the pathogenesis of acute HE. Moreover, studies using more appropriate animal models of acute liver failure (eg, both rat and mice models of acute liver failure induced by acetaminophen or thioacetamide) would have provided more convincing data on the potential role of cholesterol and bile acid signaling in brain in acute HE. Furthermore, the current dominant view of the pathogenesis of HE is that gut-derived ammonia is not adequately eliminated by the diseased liver and subsequently enters the systemic circulation, and ultimately the brain, where it exerts deleterious effects. However, it is unclear whether ammonia has any effect on altered cholesterol metabolism in acute HE or whether ammonia has any additive or synergistic effect on cholesterol accumulation in the brain after acute liver failure. An investigation of potential factors (eg, ammonia, cytokines), as well as the precise cell types involved in bile acid synthesis and cholesterol imbalance in the brain, would have provided the identification of crucial events involved in the pathogenesis of acute HE.

The study by McMillin et al¹ further showed increased cholesterol accumulation in cortical neurons of mice after acute liver failure and that the associated decrease in the bile acid signaling pathway are potentially important. McMillin et al¹ also showed that 2-HβC is able to delay the neurologic decline significantly, as well as to increase the time taken to reach hepatic coma. These promising findings strongly support an important translational implication for the treatment of HE as existing therapeutic strategies focused on liver improvement, or direct neuroprotection thus far have shown little beneficial effects. The identification of the precise molecular mechanisms and etiological factors involved in the accumulation of brain cholesterol and the associated defect in neuronal integrity after acute liver failure may yield novel pathways for neuroprotection in acute HE.