Frank Anania - Academia.edu (original) (raw)

Papers by Frank Anania

PloS one, 2014

Liver fibrosis is a growing global health problem characterized by excess deposition of fibrillar... more Liver fibrosis is a growing global health problem characterized by excess deposition of fibrillar collagen, and activation of hepatic stellate cells (HSCs). Adiponectin is known to possess anti-fibrotic properties; however a high physiological concentration and multiple forms circulating in blood prohibit clinical use. Recently, an adiponectin-like small synthetic peptide agonist (ADP355: H-DAsn-Ile-Pro-Nva-Leu-Tyr-DSer-Phe-Ala-DSer-NH2) was synthesized for the treatment of murine breast cancer. The present study was designed to evaluate the efficacy of ADP355 as an anti-fibrotic agent in the in vivo carbon tetrachloride (CCl4)-induced liver fibrosis model. Liver fibrosis was induced in eight-week old male C57BL/6J mice by CCl4-gavage every other day for four weeks before injection of a nanoparticle-conjugated with ADP355 (nano-ADP355). Control gold nanoparticles and nano-ADP355 were administered by intraperitoneal injection for two weeks along with CCl4-gavage. All mice were sacrif...

Liver Transplantation, 2001

A patient was found to have numerous granulomata 7 years after orthotopic liver transplantation f... more A patient was found to have numerous granulomata 7 years after orthotopic liver transplantation for primary sclerosing cholangitis (PSC) on a recent liver biopsy specimen. This histopathologic finding prompted a review of the literature to determine the commonality of this feature in the absence of the usual causes of granulomatous liver disease, none of which were found to be the cause of this patient's liver histopathologic state. The presence of posttransplantation granulomata is rare, and although previously reported to occur shortly after liver transplantation, this finding has not been reported previously with either PSC or vanishing bile duct syndrome. We are not aware of another case of granulomata associated with recurrent PSC or vanishing bile duct syndrome 7 years after liver transplantation.

Hepatology, 2005

Leptin upregulates collagen expression in hepatic stellate cells (HSCs), but the possible modulat... more Leptin upregulates collagen expression in hepatic stellate cells (HSCs), but the possible modulation of other actions has not been elucidated. The aim of this study was to investigate the expression and function of leptin receptors (ObR) in human HSCs and the biological actions regulated by leptin. Exposure of HSCs to leptin resulted in upregulation of monocyte chemoattractant protein 1 (MCP-1) expression. Leptin also increased gene expression of the proangiogenic cytokines vascular endothelial growth factor (VEGF) and angiopoietin-1, and VEGF was also upregulated at the protein level. Activated HSCs express ObRb and possibly other ObR isoforms. Exposure to leptin increased the tyrosine kinase activity of ObR immunoprecipitates and resulted in activation of signal transducer and activator of transcription 3. Several signaling pathways were activated by leptin in HSCs, including extracellular-signal-regulated kinase, Akt, and nuclear factor B, the latter being relevant for chemokine expression. Leptin also increased the abundance of hypoxia-inducible factor 1␣, which regulates angiogenic gene expression, in an extracellular-signal-regulated kinase-and phoshatidylinositol 3-kinase-dependent fashion.

Hepatology, 2004

Alanine aminotransferase (ALT) is a widely used index of liver integrity or hepatocellular damage... more Alanine aminotransferase (ALT) is a widely used index of liver integrity or hepatocellular damage in clinics as well as a key enzyme in intermediatary metabolism. In this study, we have cloned the complementary DNAs of murine homologues of human alanine aminotransferase 1 and 2 (ALT1 and ALT2). The deduced peptides of murine ALT1 (mALT1) and ALT2 (mALT2) share 87% and 93% identity, respectively, with their human counterparts at the amino acid level. Murine ALT genes localize to separate chromosomes, with mALT1 gene (gpt1) on chromosome 15 and mALT2 gene (gpt2) on chromosome 8. The murine gpt1 and gpt2 differ in messenger RNA expression: gpt1 is mainly expressed in liver, bowel, and white adipose tissue and gpt2 is highly expressed in muscle, liver, and white adipose tissue. Expression of recombinant mALT1 and mALT2 proteins in Escherichia coli (E. coli) produced functional enzymes that catalyze alanine transamination. The potential diagnostic value of ALT isoenzymes in liver disease was evaluated in an obese animal model. In fatty livers of obese mice, ALT2 gene expression is induced 2-fold, but ALT1 remains the same. Furthermore, in fatty liver, total hepatic ALT activity is elevated significantly by 30% whereas aspartate aminotransferase (AST) activity remains unchanged. In conclusion, these results indicate that ALT2 may be responsible for the increased ALT activity in hepatic steatosis and provide evidence that an ALT isoenzyme-specific assay may have more diagnostic value than the total ALT activity assay currently in clinical use. (HEPATOLOGY 2004;39:1297-1302.) Abbreviations: ALT, alanine aminotransferase; GPT, glutamate pyruvate transaminase; cDNA, complementary DNA; NASH, nonalcoholic steatohepatitis; EST, expressed sequence tag; PCR, polymerase chain reaction; IPTG, isopropylbeta-D-thiogalactopyranoside; AST, aspartate aminotransferase; mRNA, messenger RNA; WAT, white adipose tissue; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis. From the

Digestive Diseases and Sciences, 2007

Clinical Gastroenterology and Hepatology, 2004

Background & Aims: Hepatitis C virus (HCV) infection is more prevalent in black compared with whi... more Background & Aims: Hepatitis C virus (HCV) infection is more prevalent in black compared with white Americans. However, the natural course of HCV in black patients has not been defined. Methods: We performed a retrospective comparison of initial liver tests, HCV genotype and viral load, and liver histology findings in 87 black and 136 white American chronic hepatitis C patients who were evaluated at the University of Maryland between 1995 and 1998. The liver biopsy examinations were interpreted by using the Knodell Histologic Activity Index (HAI) criteria. Results: Black HCV patients were older (46.3 vs. 43.3 yr; P ‫؍‬ 0.004) and were more likely to be infected with HCV genotype 1 (95% vs. 75%). The modes of HCV transmission, estimated duration of HCV infection, and prevalence of alcohol abuse were similar in the 2 groups. Yet, black patients had lower mean total HAI scores (7.6 vs. 8.7; P ‫؍‬ 0.021), periportal hepatocyte necrosis scores (P ‫؍‬ 0.021), and liver fibrosis scores (P ‫؍‬ 0.049). In keeping with less hepatic necroinflammatory activity, black patients had a lower mean serum alanine transaminase (ALT) level (85.5 vs. 122.7; P ‫؍‬ 0.002). Black patients also had lower serum iron levels (P ‫؍‬ 0.009). There were no racial differences in the prevalence of increased iron studies and hepatic iron loading. Conclusions: Black chronic HCV patients have milder liver necroinflammation and fibrosis than white patients with similar HCV duration. These differences in liver histology were not explained by a variance in hepatic iron loading.

Archives of Biochemistry and Biophysics, 1999

We recently identified three areas of Sp1 binding located between ؊568 and ؊453 of the 5 flanking... more We recently identified three areas of Sp1 binding located between ؊568 and ؊453 of the 5 flanking region of the murine ␣ 2 (I) collagen promoter which are necessary for optimal activity. We now identify two additional regions of Sp1 binding located at ؊371 to ؊351 (region 4) and at ؊690 to ؊613 (region 5), which when mutated increased promoter activity in transfected rat hepatic stellate cells indicating they contain negative regulatory elements. AP-2 bound to region 4 while YY1 bound most strongly to region 5. AP-2 decreased Sp1 binding to region 4 and had a dual effect on Sp1 binding to region 5 decreasing and increasing Sp1 binding at low and high concentrations of AP-2, respectively. YY1 enhanced Sp1 binding to both regions. AP-2 inhibited or enhanced the stimulatory effect of a transfected Sp1 expression vector on the ␣ 2 (I) collagen promoter in Drosophila cells at low or high AP-2 expression, respectively. YY1 enhanced or inhibited the activation of the promoter by low or high Sp1 expression, respectively. This study identifies two negative regulatory elements in the murine ␣ 2 (I) collagen promoter and shows that AP-2 and YY1 interact with Sp1 at these sites and can inhibit the activating action of Sp1.

Archives of Biochemistry and Biophysics, 1997

development of liver fibrosis (1) is initiated by an in-Acetaldehyde activates the mouse a 2 (I) ... more development of liver fibrosis (1) is initiated by an in-Acetaldehyde activates the mouse a 2 (I) collagen pro-crease in the expression of the type I collagen genes moter and this effect is mediated in part by increased . Hepatic stellate cells are the principal source of binding of nuclear factor I (NF-I). Additional mechatype I collagen during liver fibrogenesis (3, 4). In the nisms may exist since deletions in the promoter upquiescent state, stellate cells are vitamin A fat-storing, stream to the NF-I binding site prevented enhancebut during the fibrogenesis, they become depleted of ment by acetaldehyde. Three adjacent areas of binding vitamin A and are activated into myofibroblast-like by nuclear proteins from activated hepatic stellate cells that produce type I collagen and other extracellucells were identified at 0568 to 0554 (region 1), 0542 lar matrix proteins (5, 6). When cultured on uncoated to 0518 (region 2), and 0473 to 0453 (region 3) of the plastic dishes, stellate cells are likewise activated promoter using DNase I protection analyses. Multiple within 6 to 10 days (7, 8).

Clinical Infectious Diseases, 2015

Treatment of hepatitis C virus with potent, interferon-free, direct-acting antiviral regimens wit... more Treatment of hepatitis C virus with potent, interferon-free, direct-acting antiviral regimens with no activity against hepatitis B virus (HBV) may increase the risk for HBV reactivation in coinfected patients. We present 2 cases of HBV reactivation during treatment with an all-oral regimen of simeprevir and sofosbuvir and discuss strategies to prevent HBV flare.

Toxicological sciences : an official journal of the Society of Toxicology, Jan 16, 2015

Cadmium (Cd) is present in food at low levels and accumulates in humans throughout life because i... more Cadmium (Cd) is present in food at low levels and accumulates in humans throughout life because it is not effectively excreted. Cd from smoking or occupational exposure shows adverse effects on health, but the mechanistic effect of Cd at low dietary intake levels is poorly studied. Epidemiology studies found that non-alcoholic fatty liver disease (NAFLD), common in US adults, is associated with Cd burden. In cell studies, we found that environmental low-dose Cd oxidized proteins and stimulated inflammatory signaling. However, little is known about low-dose Cd effects on liver function and associated metabolic pathways in vivo. We investigated effects of low-level Cd exposure on liver gene transcripts, metabolites, and associated metabolic pathways and function after challenging mice with Cd (10 mg/L) by drinking water. Results showed liver Cd in treated mice was similar to adult humans without occupational or smoking exposures and 10-fold higher than control mouse values. Pathway an...

American journal of physiology. Gastrointestinal and liver physiology, 2014

Ischemia-reperfusion injury (IRI) is a common clinical consequence of hepatic surgery, cardiogeni... more Ischemia-reperfusion injury (IRI) is a common clinical consequence of hepatic surgery, cardiogenic shock, and liver transplantation. A steatotic liver is particularly vulnerable to IRI, responding with extensive hepatocellular injury. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in IRI, although its role in IRI of a steatotic liver is unclear. The role of autophagy was investigated in high-fat diet (HFD)-fed mice exposed to IRI in vivo and in steatotic hepatocytes exposed to hypoxic IRI (HIRI) in vitro. Two inhibitors of autophagy, 3-methyladenine and bafilomycin A1, protected the steatotic hepatocytes from HIRI. Exendin 4 (Ex4), a glucagon-like peptide 1 analog, also led to suppression of autophagy, as evidenced by decreased autophagy-associated proteins [microtubule-associated protein 1A/1B-light chain 3 (LC3) II, p62, high-mobility group protein B1, beclin-1, and autophagy-related protein 7], reduced hepatocellular damage, and improved mitocho...

Trends in Endocrinology & Metabolism, 2015

Obesity and metabolic syndrome pose significant risk for the progression of many types of chronic... more Obesity and metabolic syndrome pose significant risk for the progression of many types of chronic illness, including liver disease. Hormones released from adipocytes, adipocytokines, associated with obesity and metabolic syndrome, have been shown to control hepatic inflammation and fibrosis. Hepatic fibrosis is the final common pathway that can result in cirrhosis, and can ultimately require liver transplantation. Initially, two key adipocytokines, leptin and adiponectin, appeared to control many fundamental aspects of the cell and molecular biology related to hepatic fibrosis and its resolution. Leptin appears to act as a profibrogenic molecule, while adiponectin has strong-antifibrotic properties. In this review, we emphasize pertinent data associated with these and other recently discovered adipocytokines that may drive or halt the fibrogenic response in the liver.

Gastroenterology, 2008

Pancreatic beta-cell mass increases in response to increased demand for insulin, but the factors ... more Pancreatic beta-cell mass increases in response to increased demand for insulin, but the factors involved are largely unknown. Glial cell line-derived neurotrophic factor (GDNF) is a growth factor that plays a role in the development and survival of the enteric nervous system. We investigated the role of GDNF in regulating beta-cell survival. Studies were performed using the beta-TC-6 pancreatic beta-cell line, isolated mouse pancreatic beta cells, and in vivo in transgenic mice that overexpress GDNF in pancreatic glia. GDNF receptor family alpha1 and c-Ret receptor expression were assessed by reverse-transcription polymerase chain reaction and immunofluorescence microscopy. Apoptosis was evaluated by assessing caspase-3 cleavage. Phosphoinositol-3-kinase signaling pathway was analyzed by Akt phosphorylation. Glucose homeostasis was assessed by performing intraperitoneal glucose tolerance tests. Insulin sensitivity was assessed using intraperitoneal injection of insulin. We demonstr...

The Journal of nutritional biochemistry, Jan 6, 2014

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (... more Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS). Up to a third of NAFLD subjects are at risk for developing nonalcoholic steatohepatitis (NASH). Many rodent models fail to replicate both MetS and NASH. The purpose of this study was to develop a reliable mouse model of NASH and MetS using a diet containing cholesterol, saturated fat and carbohydrate that is reflective of Western diets of North Americans. Experimental design: We used adult male C57BL/6 J 4- to 5-week-old mice and administered a solid diet containing 0.2% cholesterol, 45% of its calories from fat, with 30% of the fat in the form of partially hydrogenated vegetable oil. We also provided carbohydrate largely as high-fructose corn syrup equivalent in water. In a separate cohort, we gave the identical diet in the absence of cholesterol. Glucose and insulin tolerance testing was conducted throughout the feeding period. The feeding was conducted for 16 weeks, and the mic...

Seminars in Liver Disease, 2013

Hepatocellular accumulation of free fatty acids (FFAs) in the form of triglycerides constitutes t... more Hepatocellular accumulation of free fatty acids (FFAs) in the form of triglycerides constitutes the metabolic basis for the development of nonalcoholic fatty liver disease (NAFLD). Recent data demonstrate that excess FFA hepatocyte storage is likely to lead to lipotoxicity and hepatocyte apoptosis. Hence, FFA-mediated hepatocyte injury is a key contributor to the pathogenesis of nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis, obesity, type 2 diabetes, essential hypertension, and other common medical problems together comprise metabolic syndrome. Evidence suggests that peptide hormones from the L cells of the distal small intestine, which comprise the core of the enteroendocrine system (EES), play two key roles, serving either as incretins, or as mediators of appetite and satiety in the central nervous system. Recent data related to glucagon-like peptide-1 (GLP-1) and other known L-cell hormones have accumulated due to the increasing frequency of bariatric surgery, which increase delivery of bile salts to the hindgut. Bile acids are a key stimulus for the TGR5 receptor of the L cells. Enhanced bile-salt flow and subsequent EES stimulation may be central to elimination of hepatic steatosis following bariatric surgery. Although GLP-1 is a clinically relevant pharmacological analogue that drives pancreatic β-cell insulin output, GLP-1 analogues also have independent benefits via their effects on hepatocellular FFA metabolism. The authors also discuss recent data regarding the role of the major peptides released by the EES, which promote satiety and modulate energy homeostasis and utilization, as well as those that control fat absorption and intestinal permeability. Taken together, elucidating novel functions for EES-related peptides and pharmacologic development of peptide analogues offer potential far-ranging treatment for obesity-related human disease.

PLoS ONE, 2011

Background: Nonalcoholic fatty liver disease (NAFLD) is a known outcome of hepatosteatosis. Free ... more Background: Nonalcoholic fatty liver disease (NAFLD) is a known outcome of hepatosteatosis. Free fatty acids (FFA) induce the unfolded protein response (UPR) or endoplasmic reticulum (ER) stress that may induce apoptosis. Recent data indicate ER stress to be a major player in the progression of fatty liver to more aggressive lesions. Autophagy on the other hand has been demonstrated to be protective against ER stress-induced cell death. We hypothesized that exendin-4 (GLP-1 analog) treatment of fat loaded hepatocytes can reduce steatosis by autophagy which leads to reduced ER stress-related hepatocyte apoptosis.

Molecular Endocrinology, 2006

Leptin has properties of a profibrogenic cytokine. In liver, the activated hepatic stellate cell ... more Leptin has properties of a profibrogenic cytokine. In liver, the activated hepatic stellate cell (HSC) is responsible for a net production of extracellular matrix. A key molecule synthesized is the tissue inhibitor of metalloproteinase I (TIMP-1), which acts to inhibit the activity of matrix metalloproteinases. The purpose of the present study was to determine how leptin, a gp130 cytokine, orchestrates the regulation of TIMP-1 gene activation and expression. Transient transfection of primary HSCs revealed that leptin significantly increased luciferase activity of a 229-bp TIMP-1 promoter construct (TIMP-1-229). An EMSA revealed that leptin enhanced specificity protein 1 (Sp1) binding. Site-directed mutagenesis for Sp1 reduced the enhancing effect of leptin on TIMP-1 transcriptional activation, and this effect was dose dependent on the number of Sp1 sites mutated. Chromatin immunoprecipitation revealed that leptin enhanced binding of Sp1; however, inhibition of signal transducer and activator of transcription (STAT) 3 phosphorylation by AG490 also blocked Sp1 phosphorylation and significantly reduced leptinassociated TIMP-1-229 promoter activity, indicating that one mechanism for leptin-increased transcriptional activity is via phosphorylation of Sp1 and subsequent promoter binding. Finally, we demonstrate that leptin also results in intranuclear pSTAT3 binding to Sp1. We propose a novel mechanism whereby leptin-mediated TIMP-1 transcription employs a Sp1/pSTAT3dependent mechanism, one of which is a noncanonical association between Sp1 and pSTAT3. These data provide a new molecular mechanism whereby the adipocytokine leptin plays a role in complications of the metabolic syndrome.