Work-in-Progress Seminars
Every third Friday afternoon of each month from 1-2 PM
October 17, 2008 in Room S-22 at Parnassus campus
Masha Yuneva (Bishop Lab)
Effect of oncogenic transformation on cell metabolism in vivo: employing metabolomics approach in liver cancer model
Changed metabolism is one of the accepted hallmarks of cancer. We combine a metabolomics approach with microarray analysis to identify the differences in specific metabolic pathways in liver cancers induced by Myc and Ras oncogenes. This reveals the specific enzyme isoforms controlling these metabolic pathways and suggests their employment as cancer therapeutic targets.
Michael Xu (Chen Lab)
Bmi1 Functions as an Oncogene Independent of Ink4A/Arf Repression in Hepatic Carcinogenesis
Bmi1 is a polycomb family proto-oncogene that has been implicated in multiple tumor types. However, its role in HCC development has not been well-studied. Our lab recently found that Bmi1 is over-expressed in human HCC samples as well as HCC cell lines. Knock-down of Bmi1 expression in human HCC cell lines significantly perturbs cell cycle regulation and inhibits cell proliferation. In addition, we found that Bmi1 cooperates with RasV12-induced HCC formation in mice. Intriguingly, we found no evidence that Bmi1 inhibits Ink4A/Arf expression in both in vitro and in vivo systems of liver tumor development. The data demonstrate that Bmi1 functions as an oncogene and plays important roles in HCC pathogenesis independent of Ink4A/Arf repression.
November 21, 2008 in Room S-22 at Parnassus Campus
Silvia Curado (Stainier Lab)
Analyis of a zebrafish model for mitochondrial hepatopathy and liver regeneration
Oliver (O-shaped Liver) is a novel zebrafish mutant, which exhibits hepatocyte maintenance defects. This liver-specific phenotype results from a mutation in a gene encoding a mitochondrial component. The temporary loss of this protein causes a phenotype that is reversible. We are currently using this model to study liver development as well as liver recovery.
Marina Fomin (Muench Lab)
Isolation of human liver stem cells
We used epithelial cell adhesion molecule CD326 as a hepatic progenitor marker in order to isolate hepatic stem cells from the human midgestation liver. We demonstrated that CD326 is expressed by many cell types in the developing liver with a gradient of low to high expression marking hepatocyte differentiation and that co-expression of the lipopolysaccharide receptor CD14, a protein typically found on macrophages, can be used to help identify functionally distinct subsets of fetal hepatocytes and their precursors.
December 12, 2008 in Room N-527 at Parnassus Campus
Dr. Dorothy French, Senior Pathologist (Genentech, Inc.)
Targeting FGF19 in colon cancer and hepatocellular carcinoma models
Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice its involvement in human cancer is not well characterized. We have shown that FGF19 and its cognate receptor FGF receptor 4 (FGFR4) are coexpressed in primary human liver, lung and colon tumors and in a subset of human colon cancer cell lines. To test the importance of FGF19 for tumor growth, we developed an anti-FGF19 monoclonal antibody that selectively blocks the interaction of FGF19 with FGFR4. This antibody abolished FGF19-mediated activity in vitro and inhibited growth of colon tumor xenografts in vivo and effectively prevented hepatocellular carcinomas in FGF19 transgenic mice. The efficacy of the antibody in these models was linked to inhibition of FGF19-dependent activation of FGFR4, FRS2, ERK and beta-catenin. These findings suggest that the inactivation of FGF19 could be beneficial for the treatment of colon cancer, liver cancer and other malignancies involving interaction of FGF19 and FGFR4.
January 16, 2009 in Room N-721 @ Parnassus Campus
Matthew Hirschey (Verdin Lab)
Reduced fatty acid oxidation and liver steatosis in SIRT3-/- mice
Sirtuins (SIRT1-7) are a family of NAD+-dependent protein deacetylases that regulate cell survival, metabolism and longevity. SIRT3 is highly expressed in the liver and localized to the mitochondria. A recent report indicates that mice lacking both SIRT3 alleles appear phenotypically normal. However, many mitochondrial proteins were shown to be hyperacetylated in these mice. Metabolomic analysis of livers from SIRT3-/- mice revealed multiple abnormalities in lipid metabolism, including increased triglycerides and accumulation of acylcarnitines, and histological examination confirmed hepatic steatosis. Measurement of palmitate oxidation in liver extracts from wt and SIRT3-/- mice revealed a primary defect in b-oxidation in the absence of SIRT3. Mass spectrometry analysis of mitochondrial proteins in SIRT3-/- mice identified multiple enzymes in the mitochondrial b-oxidation pathway are hyperacetylated in mice lacking SIRT3. We propose that SIRT3 plays an important role in the adaptive response to fasting by upregulating b-oxidation.
Jean Publicover (Baron Lab)
Understanding the Role of Age in HBV disease outcome
HBV transgenic mouse model can be used to understand the factors that determine successful clearance of HBV versus the establishment of a chronic infection. While over 90% of adults infected with HBV are able to mount an immune response that clears the virus, over 90% of children and infants are unable to clear the virus and develop a chronic infection. I will address the importance of the liver environment in determining disease outcome and some of the differences that may account for such an altered outcome.
February 20, 2009 in Room N-721 @ Parnassus Campus
Alan Venook, MD
Update on therapy of hepatocellular carcinoma
Hepatocellular carcinoma is actually two diseases in one: underlying liver disease and cancer. This makes the treatment much more difficult and necessitates innovative trials and approaches. Such innovation includes regional and surgical therapies as well as new targeted agents.
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March 20, 2009 in Room N-721 @ Parnassus Campus
Asha Balakrishnan (Goga Lab)
Molecular Basis of Oncogene Cooperation in Liver Cancer
Hepatocellular carcinoma (HCC) is among the four leading causes of cancer-related death. HCC is often attributed to persistent infection and liver damage due to Hepatitis B or C viruses, aflatoxin B1 ingestion or chronic and excessive alcohol consumption and affects diverse populations worldwide. Despite its significance, a clearer understanding of mechanisms of liver cancer pathogenesis is limited. There is strong biological evidence that different oncogene-driven canonical signaling pathways are deregulated in liver cancer. Our work aims at understanding the molecular basis of oncogene cooperation and their contribution to development and progression of liver cancer using oncogene-driven mouse models of human liver cancer.
HCC usually presents with a poor prognosis and 6 months median survival. Currently, except for early surgical intervention or liver transplantation, no effective cures exist. Advanced tumors are rarely responsive to conventional chemotherapeutics. siRNAs are a potential novel class of therapeutic agents, with the ability to precisely inhibit disease-related genes driving tumor proliferation. Our work is also directed towards testing specific siRNAs as potential therapeutics against liver cancer.
Maribel Reyes (Benet Lab)
Effects of Uremic Serum on Uptake, Transport, and Metabolism in Rat and Human Hepatocytes
Drug transporters play an important role in drug bioavailability, excretion, and drug-drug interactions. It is not well understood why patients with chronic kidney disease show altered pharmacokinetics for non-renally excreted drugs. These changes may be due to the effects of uremic toxins on hepatic transporters and/or CYP450 metabolizing enzymes. Here we show that uremic toxins in the serum of hemodialysis patients inhibit the transport of losartan and eprosartan (class II and III drugs), but not that of propranolol (class I drug) in hepatocytes. These results suggest that uremic toxins account for the changes in pharmacokinetics of class II and III drugs but not of class I drugs.
April 17, 2009 in Room N-721 @ Parnassus Campus
Eva Herker (Ott Lab)
"Diacylglycerol Acyltransferase 1 is a Novel Host Factor for Hepatitis C Virus Replication"
The Hepatitis C Virus Core protein localizes to the surface of lipid droplets and recruits the viral replication machinery to its proximity. When expressed in cells Core protein strongly induces lipid droplets. We examined two key enzymes in the biosynthesis of lipid droplets, diacyl glycerol acyltransferases (DGAT) 1 and 2 in the context of core induced lipid droplet accumulation and in the HCV virus life cycle.
Dorothee Vogt Alatorre (Yen Lab)
The Role of the Host Protein, TIP47, in Hepatitis C Virus Replication
HCV replication is thought to occur on novel membrane structures derived from the ER. For a successful chronic infection, the virus would need to modulate the protein trafficking pathway as well as the membrane morphology of the host cell. Using a yeast-2-hybrid screening, we have found that the viral protein, NS5A, interacts with the cellular protein, TIP47, a tail-interacting protein that is involved in the host vesicular membrane transport pathway. Our hypothesis is that interaction of NS5A with TIP47 is required for establishing the required membrane-associated replication complex of hepatitis C virus. Aim of our study is to establish the significance of this protein interaction and its precise role in HCV replication.
May 15 , 2009 in Room N-721 @ Parnassus Campus
Oren K. Fix, MD
N-acetylcysteine (NAC) in non-acetaminophen acute liver failure
N-acetylcysteine (NAC) is a well-established treatment for acetaminophen-related acute liver failure. The Acute Liver Failure Study Group’s recently completed trial of NAC in non-acetaminophen related acute liver failure will be discussed.
Claus Niemann, MD & Ryutaro Hirose, MD
Ischemia-reperfusion of the Liver - can we make it any better?
June 19 , 2009 in Room N-79 @ Parnassus Campus
Amnon Schlegel, MD, PhD
A Molecular Genetic Approach to Studying Hepatic Lipid Metabolism
The rise in obesity has been mirrored by a number of related illnesses. Nonalcoholic fatty liver disease is one such common and poorly understood correlate of obesity. The initiating events in energy excess, as well as the molecular determinants of disease progression are understood poorly. A zebrafish genetic approach is described wherein mutations causing hepatic steatosis are isolated and characterized. Such a strategy of screening for the first step of a complex disease phenotype may uncover heretofore unappreciated genes involved in hepatic lipid metabolism and lead to the development of drug targets.
July 17, 2009 in Room N-729 @ Parnassus Campus
Shahab Sheikh-Bahaei (Hunt Lab)
Computational Modeling of Liver: How Zonation of Xenobiotic Metabolism Can Emerge from Local Hepatocyte Actions
Hepatocytes change protein expression levels in response to changes in their local environment. Upstream hepatocytes can communicate with downstream hepatocytes. There may also be communication of downstream with upstream hepatocytes via bile. I will present an individual-based model of liver xenobiotic metabolism in which individual hepatocytes are modeled as autonomous agents arranged on a 2D grid. An agent’s task is to protect hypothetical external “tissues” by eliminating simulated toxins. In addition, each agent strives to minimize its “energy” (internal resources) consumption while protecting the external “tissue” from damage. Each agent uses local information to choose and update a clearance strategy – the probability of eliminating an encountered simulated toxin. All agents use the same simple optimization (learning) logic. Nevertheless, they do not choose the same clearance strategy. Their strategy depends on their location and the [external] toxicity of the simulated toxin. The patterns in periportal-to-perivenous clearance strategies that emerge have striking similarities with the lobule-level zonation patterns of xenobiotic metabolism.
Jackie Maher, MD (Maher Lab)
Mechanism of hepatocyte lipotoxicity: mTOR failure and downstream consequences
Saturated fatty acids kill hepatocytes in a process that involves mTOR failure and activation of protein phosphatase 2A (PP2A). Autophagy is activated in response to saturated fatty acids, but it does not rescue hepatocytes from fatty acid-induced death. Fatty acid-induced cytotoxicity may involve alterations the cyclin-dependent kinase inhibitor p27.
August 21, 2009 in Room N-729 @ Parnassus Campus
Sanjay Kakar, MD
Hepatocellular nodules: wading through the terminology and pathologic features
September 18, 2009 in Room N-721 @ Parnassus Campus
Sandy Feng, MD
Immunosuppression Withdrawal for Pediatric Liver Transplant Recipients:
Safe or Sorry?
Immunosuppression has long been a lifelong burden carried by organ transplant recipients. A subset of liver transplant recipients can, however, maintain good organ function without immunosuppression. We, and others, are conducting clinical trials to determine the safety and efficacy of immunosuppression withdrawal. These trials are designed with intensive mechanistic studies aimed at deriving a predictive profile of the operationally tolerant transplant recipient.
October 16, 2009 in Room N-721 @ Parnassus Campus
Raymond Ng (Willenbring Lab)
The role of Trf3 and TBP in hepatocyte development
Mid-gestation hepatocyte development entails rapid expansion of nascent hepatoblasts followed by differentiation into mature hepatocytes or cholangiocytes. This differentiation program requires the coordinated expression of numerous genes which is believed to be orchestrated by sequence-specific transcription factors. The discovery of cell type-specific TAFs and TBP-related factors (TRFs) suggests that changes in the basal transcriptional machinery may contribute to differentiation by establishing cell type-specific patterns of gene expression. Our study focuses on TBP and Trf3, components of the basal transcriptional machinery, and their roles in hepatocyte development.