Nitric oxide promotes caspase‐independent hepatic stellate cell apoptosis through the generation of reactive oxygen species

Daniel A. Langer, Amitava Das, David Semela, Ningling Kang‐Decker, Helen Hendrickson, Steven F. Bronk, Zvonimir S. Katusic, Gregory J. Gores, Vijay H. Shah – 5 May 2008 – Hepatic stellate cells (HSCs) contribute to portal hypertension through multiple mechanisms that include collagen deposition, vasoconstriction, and regulation of sinusoidal structure.

Disturbed hepatic carbohydrate management during high metabolic demand in medium‐chain acyl–CoA dehydrogenase (MCAD)–deficient mice

Hilde Herrema, Terry G. J. Derks, Theo H. van Dijk, Vincent W. Bloks, Albert Gerding, Rick Havinga, Uwe J. F. Tietge, Michael Müller, G. Peter A. Smit, Folkert Kuipers, Dirk‐Jan Reijngoud – 5 May 2008 – Medium‐chain acyl–coenzyme A (CoA) dehydrogenase (MCAD) catalyzes crucial steps in mitochondrial fatty acid oxidation, a process that is of key relevance for maintenance of energy homeostasis, especially during high metabolic demand.

Activation of nuclear factor E2‐related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development

Silke Marhenke, Jutta Lamlé, Laura Elisa Buitrago‐Molina, José Manuel Fernández Cañón, Robert Geffers, Milton Finegold, Michael Sporn, Masayuki Yamamoto, Michael P. Manns, Markus Grompe, Arndt Vogel – 2 May 2008 – In tyrosinemia type 1 (HT1), accumulation of toxic metabolites results in oxidative stress and DNA damage, leading to a high incidence of hepatocellular carcinomas. Nuclear factor erythroid‐2 related factor 2 (Nrf2) is a key transcription factor important for cellular protection against oxidative stress and chemical induced liver damage.

Murine cirrhosis induces hepatocyte epithelial mesenchymal transition and alterations in survival signaling pathways

Takashi Nitta, Jae‐Sung Kim, Dagmara Mohuczy, Kevin E. Behrns – 2 May 2008 – Hepatocytes that reside in a chronically‐injured liver have altered growth responses compared to hepatocytes in normal liver. Transforming growth factor beta (TGFβ) is upregulated in the cirrhotic liver, and cirrhotic hepatocytes, unlike normal hepatocytes exposed to this cytokine, exhibit decreased apoptosis. In fetal hepatocytes, TGFβ also induces epithelial‐mesenchymal transition (EMT) and signaling changes in cell survival pathways.

Pathogenic role of natural killer T and natural killer cells in acetaminophen‐induced liver injury in mice is dependent on the presence of dimethyl sulfoxide

Mary Jane Masson, Leah D. Carpenter, Mary L. Graf, Lance R. Pohl – 2 May 2008 – Dimethyl sulfoxide (DMSO) is commonly used in biological studies to dissolve drugs and enzyme inhibitors with low solubility. Although DMSO is generally thought of as being relatively inert, it can induce biological effects that are often overlooked.

Genetic polymorphism of hepatocyte nuclear factor‐4α influences human cytochrome P450 2D6 activity

Sang Seop Lee, Eun‐Young Cha, Hyun‐Ju Jung, Ji‐Hong Shon, Eun‐Young Kim, Chang‐Woo Yeo, Jae‐Gook Shin – 2 May 2008 – Hepatocyte nuclear factor‐4 alpha (HNF4A) is an essential transcriptional regulator for many genes that are expressed preferentially in the liver. Among the important functions of the liver is drug metabolism in response to xenobiotic exposure. Recent studies have suggested that HNF4A regulates the expression of cytochrome P450 (CYP), including CYP2D6 and CYP3A4, which show large individual variations in their activities.

Genotype‐specific interactions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C

Ian Homer Y. Cua, Jason M. Hui, James G. Kench, Jacob George – 2 May 2008 – The interaction between insulin resistance (IR), steatosis and genotype to fibrosis in chronic hepatitis C virus (HCV) infection has not been comprehensively assessed. We hypothesized that IR is a key mediator for the development of both steatosis and fibrosis in 346 untreated, nondiabetic patients solely infected with either genotype 1 or 3. We examined for genotype‐specific interactions between IR, steatosis and fibrosis by performing subgroup analyses.

Beyond insulin resistance: Innate immunity in nonalcoholic steatohepatitis

Jacquelyn J. Maher, Pablo Leon, James C. Ryan – 2 May 2008 – Obesity is an inflammatory disorder characterized by heightened activity of the innate immune system. Innate immune activation is central to the development of obesity‐related insulin resistance; it also plays an important role in obesity‐related tissue damage, such as that seen in atherosclerosis. Recent research has implicated the innate immune system in the pathophysiology of obesity‐related liver disease.

Natural killer T cell dysfunction in CD39‐null mice protects against concanavalin A–induced hepatitis

Guido Beldi, Yan Wu, Yara Banz, Michael Nowak, Lindsay Miller, Keiichi Enjyoji, Arvand Haschemi, Gennady G. Yegutkin, Daniel Candinas, Mark Exley, Simon C. Robson – 2 May 2008 – Concanavalin A (Con A)–induced injury is an established natural killer T (NKT) cell–mediated model of inflammation that has been used in studies of immune liver disease. Extracellular nucleotides, such as adenosine triphosphate, are released by Con A–stimulated cells and bind to specific purinergic type 2 receptors to modulate immune activation responses.

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