PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease

Elizabeth K. Speliotes, Johannah L. Butler, Cameron D. Palmer, Benjamin F. Voight, the GIANT Consortium the MIGen Consortium, the NASH CRN, Joel N. Hirschhorn – 26 August 2010 – Single nucleotide polymorphisms (SNPs) near 7 loci have been associated with liver function tests or with liver steatosis by magnetic resonance spectroscopy. In this study we aim to test whether these SNPs influence the risk of histologically‐confirmed nonalcoholic fatty liver disease (NAFLD).

Transforming growth factor‐beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth

Serif Senturk, Mine Mumcuoglu, Ozge Gursoy‐Yuzugullu, Burcu Cingoz, Kamil Can Akcali, Mehmet Ozturk – 26 August 2010 – Senescence induction could be used as an effective treatment for hepatocellular carcinoma (HCC). However, major senescence inducers (p53 and p16Ink4a) are frequently inactivated in these cancers. We tested whether transforming growth factor‐β (TGF‐β) could serve as a potential senescence inducer in HCC. First, we screened for HCC cell lines with intact TGF‐β signaling that leads to small mothers against decapentaplegic (Smad)‐targeted gene activation.

Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease

Brent A. Neuschwander‐Tetri, Jeanne M. Clark, Nathan M. Bass, Mark L. Van Natta, Aynur Unalp‐Arida, James Tonascia, Claudia O. Zein, Elizabeth M. Brunt, David E. Kleiner, Arthur J. McCullough, Arun J. Sanyal, Anna Mae Diehl, Joel E. Lavine, Naga Chalasani, Kris V. Kowdley, NASH Clinical Research Network – 26 August 2010 – The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) was formed to conduct multicenter studies on the etiology, contributing factors, natural history, and treatment of nonalcoholic steatohepatitis (NASH).

Preclinical assessment of simultaneous targeting of epidermal growth factor receptor (ErbB1) and ErbB2 as a strategy for cholangiocarcinoma therapy

Zichen Zhang, Regina A. Oyesanya, Deanna J. W. Campbell, Jorge A. Almenara, Jennifer L. DeWitt, Alphonse E. Sirica – 26 August 2010 – Overexpression of epidermal growth factor receptor (ErbB1) and/or ErbB2 has been implicated in the pathogenesis of cholangiocarcinoma, suggesting that combined ErbB1/ErbB2 targeting might serve as a target‐based therapeutic strategy for this highly lethal cancer.

Patatin‐like phospholipase domain‐containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease

Weiqin Chen, Benny Chang, Lan Li, Lawrence Chan – 26 August 2010 – PNPLA3 (adiponutrin), a novel patatin‐like phospholipase domain‐containing enzyme, is expressed at high level in fat, but also in other tissues including liver. Polymorphisms in PNPLA3 have been linked to obesity and insulin sensitivity. Notably, a nonsynonymous variant rs738409(G) allele of the PNPLA3 gene was found to be strongly associated with both nonalcoholic and alcoholic fatty liver disease. We have generated Pnpla3−/− mice by gene targeting.

Epithelial‐to‐mesenchymal transition of murine liver tumor cells promotes invasion

Wei Ding, Hanning You, Hien Dang, Francis LeBlanc, Vivian Galicia, Shelly C. Lu, Bangyan Stiles, C. Bart Rountree – 26 August 2010 – Epithelial‐to‐mesenchymal transition (EMT) is predicted to play a critical role in metastatic disease in hepatocellular carcinoma. In this study, we used a novel murine model of EMT to elucidate a mechanism of tumor progression and metastasis. A total of 2 × 106 liver cells isolated from Ptenloxp/loxp/Alb‐Cre+ mice, expanded from a single CD133+CD45− cell clone, passage 0 (P0), were sequentially transplanted to obtain two passages of tumor cells, P1 and P2.

p130Cas, Crk‐associated substrate plays essential roles in liver development by regulating sinusoidal endothelial cell fenestration

Tatsuya Tazaki, Takaaki Sasaki, Kenta Uto, Norimasa Yamasaki, Satoshi Tashiro, Ryuichi Sakai, Minoru Tanaka, Hideaki Oda, Zen‐Ichiro Honda, Hiroaki Honda – 26 August 2010 – p130Cas, Crk‐associated substrate (Cas), is an adaptor/scaffold protein that plays a central role in actin cytoskeletal reorganization. We previously showed that mice in which Cas was deleted (Cas−/−) died in utero because of early cardiovascular maldevelopment.

Biliary apotopes and anti‐mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis

Ana Lleo, Christopher L. Bowlus, Guo‐Xiang Yang, Pietro Invernizzi, Mauro Podda, Judy Van de Water, Aftab A. Ansari, Ross L. Coppel, Howard J. Worman, Gregory J. Gores, M. Eric Gershwin – 26 August 2010 – Our understanding of primary biliary cirrhosis (PBC) has been significantly enhanced by the rigorous dissection of the multilineage T and B cell response against the immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC‐E2). PDC‐E2 is a ubiquitous protein present in mitochondria of nucleated cells.

Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: A narrative review and clinical perspective of prospective data

Nazim Ghouri, David Preiss, Naveed Sattar – 26 August 2010 – In recent years, a strong link has been established between nonalcoholic fatty liver disease (NAFLD) and the pathogenesis of type 2 diabetes mellitus. The potential role of NAFLD in cardiovascular disease (CVD) has also attracted interest. Published studies have tended to use biochemical and imaging surrogate markers of NAFLD, such as elevated gamma glutamyl transpeptidase (GGT) and alanine aminotransferase (ALT) and fatty liver on ultrasound, when investigating associations with incident CVD events.

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