Hepatology Commons^™

The Autophagic Protein P62 Is A Target Of Reactive Aldehydes In Human And Murine Cholestatic Liver Disease, Colin T Shearn, Aimee L Anderson, Michael W Devereux, David J Orlicky, Cole Michel, Dennis R Petersen, Colin G Miller, Sanjiv Harpavat, Edward E Schmidt, Ronald J Sokol

Faculty, Staff and Students Publications

Inflammatory cholestatic liver diseases, including Primary Sclerosing Cholangitis (PSC), are characterized by periportal inflammation with progression to cirrhosis. The objective of this study was to examine interactions between oxidative stress and autophagy in cholestasis. Using hepatic tissue from male acute cholestatic (bile duct ligated) as well as chronic cholestatic (Mdr2KO) mice, localization of oxidative stress, the antioxidant response and induction of autophagy were analyzed and compared to human PSC liver. Concurrently, the ability of reactive aldehydes to post-translationally modify the autophagosome marker p62 was assessed in PSC liver tissue and in cell culture. Expression of autophagy markers was upregulated in …

Pathologic Inflammation In Malnutrition Is Driven By Proinflammatory Intestinal Microbiota, Large Intestine Barrier Dysfunction, And Translocation Of Bacterial Lipopolysaccharide, Grace T Patterson, Elvia Y Osorio, Alex Peniche, Sara M Dann, Erika Cordova, Geoffrey A Preidis, Ji Ho Suh, Ichiaki Ito, Omar A Saldarriaga, Michael Loeffelholz, Nadim J Ajami, Bruno L Travi, Peter C Melby

Faculty, Staff and Students Publications

Acute malnutrition, or wasting, is implicated in over half of all deaths in children under five and increases risk of infectious disease. Studies in humans and preclinical models have demonstrated that malnutrition is linked to an immature intestinal microbiota characterized by increased prevalence of Enterobacteriaceae. Observational studies in children with moderate acute malnutrition (MAM) have also observed heightened systemic inflammation and increased circulating bacterial lipopolysaccharides (LPS; endotoxin). However, the mechanisms that underpin the systemic inflammatory state and endotoxemia, and their pathophysiological consequences, remain uncertain. Understanding these pathophysiological mechanisms is necessary to design targeted treatments that will improve the unacceptable rate …

Crosstalk Between Beta-Adrenergic And Insulin Signaling Mediates Mechanistic Target Of Rapamycin Hyperactivation In Liver Of High-Fat Diet-Fed Male Mice, Sadia Ashraf, Nadia Ashraf, Gizem Yilmaz, Romain Harmancey

Faculty, Staff and Student Publications

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. While increased nutrient intake and sympathetic activity have been associated with the disease, the pathogenesis of NAFLD remains incompletely understood. We investigated the impact of the interaction of high dietary fat and sugar intake with increased beta-adrenergic receptor (β-AR) signaling on the activity of nutrient-sensing pathways and fuel storage in the liver. C57BL/6J mice were fed a standard rodent diet (STD), a high-fat diet (HFD), a high-fat/high-sugar Western diet (WD), a high-sugar diet with mixed carbohydrates (HCD), or a high-sucrose diet (HSD). After 6 week on …

Crosstalk Between Beta-Adrenergic And Insulin Signaling Mediates Mechanistic Target Of Rapamycin Hyperactivation In Liver Of High-Fat Diet-Fed Male Mice, Sadia Ashraf, Nadia Ashraf, Gizem Yilmaz, Romain Harmancey

Faculty, Staff and Student Publications

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. While increased nutrient intake and sympathetic activity have been associated with the disease, the pathogenesis of NAFLD remains incompletely understood. We investigated the impact of the interaction of high dietary fat and sugar intake with increased beta-adrenergic receptor (β-AR) signaling on the activity of nutrient-sensing pathways and fuel storage in the liver. C57BL/6J mice were fed a standard rodent diet (STD), a high-fat diet (HFD), a high-fat/high-sugar Western diet (WD), a high-sugar diet with mixed carbohydrates (HCD), or a high-sucrose diet (HSD). After 6 week on …

Sirt3 Is Required For Liver Regeneration But Not For The Beneficial Effect Of Nicotinamide Riboside, Sarmistha Mukherjee, James Mo, Lauren M Paolella, Caroline E Perry, Jade Toth, Mindy M Hugo, Qingwei Chu, Qiang Tong, Karthikeyani Chellappa, Joseph A Baur

Children’s Nutrition Research Center Staff Publications

Liver regeneration is critical to survival after traumatic injuries, exposure to hepatotoxins, or surgical interventions, yet the underlying signaling and metabolic pathways remain unclear. In this study, we show that hepatocyte-specific loss of the mitochondrial deacetylase SIRT3 drastically impairs regeneration and worsens mitochondrial function after partial hepatectomy. Sirtuins, including SIRT3, require NAD as a cosubstrate. We previously showed that the NAD precursor nicotinamide riboside (NR) promotes liver regeneration, but whether this involves sirtuins has not been tested. Here, we show that despite their NAD dependence and critical roles in regeneration, neither SIRT3 nor its nuclear counterpart SIRT1 is required for …

Hypoxia-Inducible Factor–1Α–Dependent Induction Of Mir122 Enhances Hepatic Ischemia Tolerance, Cynthia Ju, Meng Wang, Eunyoung Tak, Boyun Kim, Christoph Emontzpohl, Yang Yang, Xiaoyi Yuan, Huban Kutay, Yafen Liang, David R Hall, Wasim A Dar, J Steve Bynon, Peter Carmeliet, Kalpana Ghoshal, Holger K Eltzschig

Faculty, Staff and Student Publications

Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction …

Vertical Sleeve Gastrectomy Confers Metabolic Improvements By Reducing Intestinal Bile Acids And Lipid Absorption In Mice, Lili Ding, Eryun Zhang, Qiaoling Yang, Lihua Jin, Kyle M Sousa, Bingning Dong, Yangmeng Wang, Jui Tu, Xiaoxiao Ma, Jingyan Tian, Hongli Zhang, Zhipeng Fang, Ana Guan, Yixin Zhang, Zhengtao Wang, David D Moore, Li Yang, Wendong Huang

Faculty, Staff and Students Publications

Vertical sleeve gastrectomy (VSG) is a highly effective bariatric surgery that sustainably treats obesity and type 2 diabetes (T2D). However, the underlying mechanisms governing its metabolic benefits remain unclear. In this study, we have used four different genetically modified mouse lines to understand the link between bile acid circulation and metabolic effects of VSG. Instead of directly activating the nuclear bile acid receptor farnesoid X receptor (Fxr) in the liver or intestine, VSG reduces intestinal levels of bile acids, thereby decreasing fat absorption in the intestine. Given the rising popularity of bariatric surgeries to treat obesity and associated T2D, the …

Hypoxia-Inducible Factor (Hif)-2Α Reprograms Liver Macrophages To Protect Against Acute Liver Injury Via The Production Of Interleukin-6, Rachel Y Gao, Meng Wang, Qihui Liu, Dechun Feng, Yankai Wen, Yang Xia, Sean P Colgan, Holger K Eltzschig, Cynthia Ju

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure, resulting in death or liver transplantation in more than one third of patients in the United States. The effectiveness of the only antidote, N-acetylcysteine, declines rapidly after APAP ingestion, long before patients are admitted to the clinic with symptoms of severe liver injury. The direct hepatotoxicity of APAP triggers a cascade of innate immune responses that may exacerbate or limit the progression of tissue damage. A better understanding of this complex mechanism will help uncover targets for therapeutic interventions.

APPROACH AND RESULTS: We observed that …

Methyl-Sensing Nuclear Receptor Liver Receptor Homolog-1 Regulates Mitochondrial Function In Mouse Hepatocytes, Sungwoo Choi, Bingning Dong, Chih-Chun Janet Lin, Mi Jeong Heo, Kang Ho Kim, Zhen Sun, Martin Wagner, Nagireddy Putluri, Jae Myoung Suh, Meng C Wang, David D Moore

Faculty, Staff and Students Publications

Liver receptor homologue-1 (LRH-1; NR5A2) is a nuclear receptor that regulates metabolic homeostasis in the liver. Previous studies identified phosphatidylcholines as potential endogenous agonist ligands for LRH-1. In the liver, distinct subsets of phosphatidylcholine species are generated by two different pathways: choline addition to phosphatidic acid via the Kennedy pathway, or trimethylation of phosphatidylethanolamine via Phosphatidylethanolamine N-methyl Transferase (PEMT). Here we report that a PEMT - LRH-1 pathway specifically couples methyl metabolism and mitochondrial activities in hepatocytes. We show that the loss of Lrh-1 reduces mitochondrial number, basal respiration, beta-oxidation and ATP production in hepatocytes, and decreases expression of mitochondrial …

Complement Factor D Protects Mice From Ethanol-Induced Inflammation And Liver Injury., Rebecca L Mccullough, Megan R Mcmullen, Megan M Sheehan, Kyle L Poulsen, Sanjoy Roychowdhury, Dian J Chiang, Michele T Pritchard, Juan Caballeria, Laura E Nagy

Articles, Abstracts, and Reports

Complement plays a crucial role in microbial defense and clearance of apoptotic cells. Emerging evidence suggests complement is an important contributor to alcoholic liver disease. While complement component 1, Q subcomponent (C1q)-dependent complement activation contributes to ethanol-induced liver injury, the role of the alternative pathway in ethanol-induced injury is unknown. Activation of complement via the classical and alternative pathways was detected in alcoholic hepatitis patients. Female C57BL/6J [wild type (WT)], C1q-deficient ( C1qa

Effect Of Stem Cell And Vitamin E For The Reduction Of Liver Fibrosis, Sulaiman Shams, Salman Khan, Muhammad Ayaz, Haider Ali Khan, Hammad Hassan

Centre for Regenerative Medicine & Stem Cell Research

Liver disease is seventh leading cause of death worldwide. In the past, liver transplantation was thought to be the only treatment for the last stage liver disease but currently stem cells therapy is an alternative method for the treatment of liver disease. So mesenchymal stem cells (MSCs) transplantation is one of the best tool for treatment of liver disease. The aim of the current study was to investigate the combined effect of vitamin E (Vit E) and MSCs on liver fibrosis. Liver damage was induced in male albino mice intraperitoneally with carbon tetrachloride (CCl4) twice a week for six weeks. …

Bioluminescent Imaging Reveals Divergent Viral Pathogenesis In Two Strains Of Stat1-Deficient Mice, And In Αßγ Interferon Receptor-Deficient Mice, Tracy Jo Pasieka, Lynne Collins, Megan A. O'Connor, Yufei Chen, Zachary M. Parker, Brent L. Berwin, David R. Piwnica-Worms, David A. Leib

Dartmouth Scholarship

Pivotal components of the IFN response to virus infection include the IFN receptors (IFNR), and the downstream factorsignal transducer and activator of transcription 1 (Stat1). Mice deficient for Stat1 and IFNR (Stat12/2 and IFNaßcR2/2 mice) lack responsiveness to IFN and exhibit high sensitivity to various pathogens. Here we examined herpes simplex virus type 1 (HSV-1) pathogenesis in Stat12/2 mice and in IFNaßcR2/2 mice following corneal infection and bioluminescent imaging. Two divergent and paradoxical patterns of infection were observed. Mice with an N-terminal deletion in Stat1 (129Stat12/2(N-term)) had transient infection of the liver and spleen, but succumbed to encephalitis by day …

Tissue-Specific Regulation Of Mouse Microrna Genes In Endoderm-Derived Tissues., Yan Gao, Jonathan Schug, Lindsay B Mckenna, John Le Lay, Klaus H Kaestner, Linda E Greenbaum

Department of Cancer Biology Faculty Papers

MicroRNAs fine-tune the activity of hundreds of protein-coding genes. The identification of tissue-specific microRNAs and their promoters has been constrained by the limited sensitivity of prior microRNA quantification methods. Here, we determine the entire microRNAome of three endoderm-derived tissues, liver, jejunum and pancreas, using ultra-high throughput sequencing. Although many microRNA genes are expressed at comparable levels, 162 microRNAs exhibited striking tissue-specificity. After mapping the putative promoters for these microRNA genes using H3K4me3 histone occupancy, we analyzed the regulatory modules of 63 microRNAs differentially expressed between liver and jejunum or pancreas. We determined that the same transcriptional regulatory mechanisms govern tissue-specific …