LAUSR

he article by McMillin et al in the current issue Tof 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 al 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 al 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-b-cyclodextrin (2-HbC), 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 al documented that treatment of mice