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Gene Expression

Brenton R Ware, Grace E Brown, Valerie Y Soldatow, Edward L LeCluyse, Salman R Khetani
Testing drugs in isogenic rodent strains to satisfy regulatory requirements is insufficient for derisking organ toxicity in genetically diverse human populations; in contrast, advances in mouse genetics can help mitigate these limitations. Compared to the expensive and slower in vivo testing, in vitro cultures enable the testing of large compound libraries towards prioritizing lead compounds and selecting an animal model with human-like response to a compound. In the case of the liver, a leading cause of drug attrition, isolated primary mouse hepatocytes (PMHs) rapidly decline in function within current culture platforms, which restricts their use for assessing the effects of longer-term compound exposure...
July 24, 2019: Gene Expression
Benjamin L Woolbright, Hartmut Jaeschke
Cholestasis results in blockage of bile flow whether the point of obstruction occurs extrahepatically or intrahepatically. Bile acids are a primary constituent of bile, and thus one of the primary outcomes is acute retention of bile acids in hepatocytes. Bile acids are normally secreted into the biliary tracts and then released into the small bowel before recirculating back to the liver. Retention of bile acids has long been hypothesized to be a primary cause of the associated liver injury that occurs during acute or chronic cholestasis...
June 28, 2019: Gene Expression
Nathan Werneburg, Gregory J Gores, Rory L Smoot
The Hippo pathway, and it's effector protein YAP (a transcriptional co-activator) have been identified as important in the biology of both hepatocellular carcinoma and cholangiocarcinoma. First identified as a tumor suppressor pathway in Drosophila, the understanding of the mammalian YAP signaling and it's regulation continues to expand. In its "on" function the canonical regulatory Hippo pathway, a well described serine-threonine kinase module, regulates YAP function by restricting its subcellular localization to the cytoplasm...
June 28, 2019: Gene Expression
Jia-Zhen Zhang, Jing-Jing Cai, Yao Yu, Zhi-Gang She, Hongliang Li
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease and a major cause of related complications such as cirrhosis and hepatocellular carcinoma (HCC). NAFLD progresses through the stages of simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and HCC. However, NAFLD usually cannot be diagnosed in a timely manner, which is largely attributed to the asymptomatic features of NAFLD patients and the lack of an effective and accurate noninvasive screening approach. Although liver biopsy has been recognized as a gold standard for diagnosing NAFLD, this approach is not suitable for screening and monitoring NAFLD because of its high cost and invasiveness...
April 22, 2019: Gene Expression
Ming-Ming Chen, Jing-Jing Cai, Yao Yu, Zhi-Gang She, Hongliang Li
Nonalcoholic steatohepatitis (NASH) is the second leading cause of liver transplantation in the United States with a high risk of liver-related morbidities and mortality. Given the global burden of NASH, development of appropriate therapeutic strategies is an important clinical need. Where applicable, lifestyle modification remains the primary recommendation for the treatment of NASH, even though such changes are difficult to sustain and even insufficient to cure NASH. Bariatric surgery resolves NASH in such patients where lifestyle modifications have failed, and is recommended for morbidly obese patients with NASH...
April 2, 2019: Gene Expression
Preeti Pathak, John Y L Chiang
Sterol 12α-hydroxylase (CYP8B1) is required for synthesis of cholic acid in the classic bile acid synthesis pathway and plays a role in dyslipidemia and insulin resistance. However, the mechanism of the involvement of Cyp8b1 in dyslipidemia and insulin resistance is not known. CYP8B1 mRNA and protein expression are elevated in diabetic and obese ( db/db ) mouse liver. In this study adenovirus-mediated transduction of CYP8B1 was used to study the effect of Cyp8b1 on lipid metabolism in mice. Results show that Ad-Cyp8b1 increased 12α-hydroxylated bile acids and induced sterol regulatory element binding protein 1c (Srebp1c)-mediated lipogenic gene expression...
March 19, 2019: Gene Expression
Hua Yang, Hong-Min Ni, Wen-Xing Ding
Studies using genetic mouse models that have defective autophagy have led to the conclusion that macroautophagy/autophagy serves as a tumor suppressor. One of such models is the liver-specific Atg5 or Atg7 knockout mice, and these knockout mice develop spontaneous liver tumors. It has been generally agreed that p62-mediated Nrf2 activation plays a critical role in promoting autophagy deficiencyinduced liver injury and liver tumorigenesis. The mechanisms of how persistent Nrf2 activation induces liver injury and tumorigenesis are incompletely known...
January 28, 2019: Gene Expression
Tirthadipa Pradhan-Sundd, Satdarshan Pal Monga
The term blood bile barrier (BBlB) refers to the physical structure within a hepatic lobule that compartmentalizes and hence segregates sinusoidal blood from canalicular bile. Thus, this barrier provides physiological protection in the liver, shielding the hepatocytes from bile toxicity and restricting the mixing of blood and bile. BBlB is primarily composed of tight junctions; however, adherens junction, desmosomes, gap junctions and hepatocyte bile transporters also contribute to the barrier function of the BBlB...
January 15, 2019: Gene Expression
Rong Zhang, Alexander T Kikuchi, Toshimasa Nakao, Jacquelyn O Russell, Morgan E Preziosi, Minakshi Poddar, Sucha Singh, Aaron W Bell, Steven G England, Satdarshan P Monga
Background : Alterations in the Wnt signaling pathway including those impacting hepatic stellate cells (HSC) have been implicated in liver fibrosis. Methods : In the current study, we first examined the expression of Wnt genes in human HSC (HHSC) after treatment with a pro-fibrogenic factor TGFβ1. Next, we generated HSC-specific Wntless (Wls) knockout (KO) using the Lrat-cre and Wls-floxed mice. KO and littermate controls (CON) were characterized for any basal phenotype and subjected to two liver fibrosis protocols...
September 20, 2018: Gene Expression
Jie Zhao, Maura O'Neil, Anusha Vittal, Steven A Weinman, Irina Tikhanovich
Alcohol is a well-established risk factor for hepatocellular carcinoma, but the mechanisms are not well understood. Several studies suggested that alcohol promotes tumor growth by altering immune cell phenotypesin the liver.Arginine methylation is a common posttranslational modification generated mostly by a single protein,PRMT1. In myeloid cells PRMT1 is a key regulator of immune response. Myeloid specific PRMT1 knockout mice are hyper-responsive to LPS and deficient in PPARγ-dependent macrophage M2 polarization...
September 18, 2018: Gene Expression
Sirisha Achanta, Aalap Verma, Ankita Srivastava, Harshavardhan Nilakantan, Jan B Hoek, Rajanikanth Vadigepalli
The analysis of molecular states of individual cells, as defined by their mRNA expression profiles and protein composition, has gained widespread interest in studying biological phenomena ranging from embryonic development to homeostatic tissue function and genesis and evolution of cancers. Although the molecular content of individual cells in a tissue can vary widely, their molecular states tend to be constrained within a transcriptional landscape partly described by the canonical archetypes of a population of cells...
September 6, 2018: Gene Expression
Akiko Matsuda, Kaori Ishiguro, Irene K Yan, Tushar Patel
Aberrant activation of β -catenin signaling is frequently observed in hepatocellular cancer. Although Wnt/ β-catenin signaling can be targeted by Vitamin D, therapeutic use of Vitamin D for this purpose is not currently established. We evaluated the therapeutic use of Vitamin D or its analogues using a synthetic transgenic mouse of hepato-carcinogenesis induced by mutant β-catenin, and MET overexpression in which 75% of mice develop well differentiated HCC within 8 weeks in the absence of fibrosis. Vitamin D receptor expression was similar in both tumoral and non-tumoral tissue...
August 29, 2018: Gene Expression
Nandini Agarwal, Branimir Popovic, Nicole J Martucci, Nicolas A Fraunhoffer, Alejandro Soto-Gutierrez
Directed differentiation of hepatocytes from induced pluripotent stem cells (iPSCs) holds promise as source material for treating some liver disorders. The unlimited availability of perfectly differentiated iPSC-derived hepatocytes will dramatically facilitate cell therapies. While systems to manufacture large quantities of iPSCs-derived cells have been developed, we have been unable to generate and maintain stable and mature adult liver cells ex vivo. This short review highlights important challenges and possible solutions to the current state of hepatocyte biofabrication for cellular therapies to treat liver diseases...
August 24, 2018: Gene Expression
Chao Hou, Wenwen Feng, Shan Wei, Yulin Wang, Xiaoyi Xu, Jin Wei, Ziliang Ma, Yongsheng Du, Jialin Guo, Yu He, Fanyun Kong, Renxian Tang, Kuiyang Zheng
Non-alcoholic fatty liver disease (NAFLD) is a global health problem characterized with excessive accumulation of fat in the liver without effect of other pathological factors included hepatitis infection and alcohol abuse. Current studies indicate that gene factors play important roles in the development of NAFLD. However, the molecular characteristics of differentially expressed genes (DEGs) and associated mechanisms with NAFLD have not been well elucidated. Using two microarray data associated with the gene expression profiling in liver tissues of NAFLD mice models, we identified and selected several common key DEGs that contributed to NAFLD...
August 22, 2018: Gene Expression
Stephanie Grant, Matthew McMillin, Gabriel Frampton, Anca D Petrescu, Elaina Williams, Victoria Jaeger, Jessica Kain, Sharon DeMorrow
Acute liver failure is a devastating consequence of hepatotoxic liver injury that can lead to the development of hepatic encephalopathy. There is no consensus on the best model to represent these syndromes in mice, and therefore the aim of this study was to classify hepatic and neurological consequences of azoxymethane- and thioacetamide-induced liver injury. Azoxymethane-treated mice were euthanized at time points representing absence of minor and significant stages of neurological decline. Thioacetamide-treated mice had tissue collected at up to 3 days following daily injections...
August 22, 2018: Gene Expression
Yifeng Wang, David Matye, Nga Nguyen, Yuxia Zhang, Tiangang Li
Cysteine dioxygenase 1 (CDO1) converts cysteine to cysteine sulfinic acid, which can be further converted by cysteine sulfinic acid decarboxylase (CSAD) to hypotaurine for taurine production. This cysteine catabolic pathway plays a major role in regulating hepatic cysteine homeostasis. Furthermore, taurine is used for bile acid conjugation, which enhances bile acid solubility and physiological function in the gut. Recent studies show that this cysteine catabolic pathway is repressed by bile acid signaling, but the molecular mechanisms have not been fully elucidated...
August 22, 2018: Gene Expression
Mehwish Khaliq, Sungjin Ko, Yinzi Liu, Hualin Wang, Yonghua Sun, Lila Solnica-Krezel, Donghun Shin
After liver injury, regeneration manifests as either (1) hepatocytes proliferating to restore the lost hepatocyte mass or (2) if hepatocyte proliferation is compromised, biliary epithelial cells (BECs) dedifferentiating into liver progenitor cells (LPCs), which subsequently differentiate into hepatocytes. Following pharmacogenetic ablation of hepatocytes in Tg(fabp10a:CFP-NTR) zebrafish, resulting in severe liver injury, signal transducer and activator of transcription 3 (Stat3) and its target gene and negative regulator, socs3a, were upregulated in regenerating livers...
August 22, 2018: Gene Expression
Elsa Ghurburrun, Ivan Borbath, Frédéric P Lemaigre, Patrick Jacquemin
The liver and pancreas are closely associated organs that share a common embryological origin. They display amphicrine properties and have similar exocrine organization with parenchymal cells, namely, hepatocytes and acinar cells, secreting bile and pancreatic juice into the duodenum via a converging network of bile ducts and pancreatic ducts. Here we compare and highlight the similarities of molecular mechanisms leading to liver and pancreatic cancer development. We suggest that unraveling tumor development in an organ may provide insight into our understanding of carcinogenesis in the other organ...
August 22, 2018: Gene Expression
Laurent Ehrlich, April O'Brien, Chad Hall, Tori White, Lixian Chen, Nan Wu, Julie Venter, Marinda Scrushy, Muhammad Mubarak, Fanyin Meng, David Dostal, Chaodong Wu, Terry C Lairmore, Gianfranco Alpini, Shannon Glaser
α7-nAChR is a nicotinic acetylcholine receptor [specifically expressed on hepatic stellate cells (HSCs), Kupffer cells, and cholangiocytes] that regulates inflammation and apoptosis in the liver. Thus, targeting α7-nAChR may be therapeutic in biliary diseases. Bile duct ligation (BDL) was performed on wild-type (WT) and α7-nAChR-/- mice. We first evaluated the expression of α7-nAChR by immunohistochemistry (IHC) in liver sections. IHC was also performed to assess intrahepatic bile duct mass (IBDM), and Sirius Red staining was performed to quantify the amount of collagen deposition...
August 22, 2018: Gene Expression
Morgan Preziosi, Minakshi Poddar, Sucha Singh, Satdarshan P Monga
Activation of the Wnt/β-catenin signaling is reported in large subsets of hepatocellular carcinoma (HCC). Upregulation of Wnt genes is one contributing mechanism. In the current study, we sought to address the role of hepatocyte-derived Wnts in a model of hepatic injury, fibrosis, and carcinogenesis. We subjected hepatocyte-specific Wntless knockout mice (HP-KO), unable to secrete Wnts from hepatocytes, and littermate controls (HP-CON) to diethylnitrosamine and carbon tetrachloride (DEN/CCl4) and harvested at 3, 5, and 6 months for histological and molecular analysis...
August 22, 2018: Gene Expression
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