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PubMed2004

Probiotics: a potential target for the prevention and treatment of steatohepatitis.

The accumulation of fat in hepatocytes with a necroinflammatory component-steatohepatitis-that may or may not have associated fibrosis is becoming a frequent lesion. Although steatohepatitis is currently recognized to be a leading cause of cryptogenic cirrhosis, the pathogenesis has not been fully elucidated. Among the various factors implicated, intestinal bacterial overgrowth may play a role. Indeed, various rat models of intestinal bacterial overgrowth have been associated with liver lesions similar to NASH, and bacterial overgrowth has been observed significantly more often in patients with NASH compared with control subjects. The authors discuss the relationship among intestinal bacterial overgrowth, steatohepatitis development, and probiotic treatment.

Animals↗

PubMed2006

The epidemiology of nonalcoholic fatty liver disease in adults.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that has been shown to progress to cirrhosis and hepatocellular carcinoma. This article reviews the prevalence of NAFLD and the factors associated this disorder, and with the more advanced stages of NAFLD, including nonalcoholic steatohepatitis (NASH) and fibrosis. In the general population, the estimated prevalence ranges from 3% to 24%, with most estimates in the 6% to 14% range. NAFLD is extremely common among patients undergoing bariatric surgery, ranging from 84% to 96%. In these patients, 25% to 55% have NASH, 34% to 47% have fibrosis, and 2% to 12% have bridging fibrosis or cirrhosis. NAFLD appears to be most strongly associated with obesity, and insulin resistance states including diabetes and with other features of the metabolic syndrome, such as high triglycerides and low HDL. It appears to be more common in men, and it increases with increasing age and after menopause. Some data suggest that Mexican Americans are more likely to have NAFLD and blacks are less likely compared with non-Hispanic whites. More advanced stages of NAFLD are associated with older age, higher body mass index, diabetes, hypertension, high triglycerides, and/or insulin resistance. An AST/ALT ratio greater >1 may also indicate more severe disease. Although hepatocellular carcinoma can occur in the setting of NAFLD, the risk factors for hepatocellular carcinoma in the setting of NAFLD have not been established. More prospective studies are needed to determine the true risk factors for the development and progression of NAFLD to help identify patients at highest risk who might benefit from treatment trials.

Carcinoma, Hepatocellular↗

PubMed2006

Genetic influences in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a metabolic liver disease with widely variable phenotypes extending from simple steatosis, through nonalcoholic steatohepatitis (NASH) to cirrhosis and hepatocellular carcinoma. Inevitably, this reflects the interplay of well-recognized environmental factors and disease associations such as obesity and insulin resistance with host genetic factors, which are polygenic or complex in nature. Most of the observed phenotypic variability will probably be explained by variations in single nucleotide polymorphism frequency, although knowledge of the effect of most polymorphisms on biologic function is currently limited. Several observational studies of kindred with NASH suggest a genetic contribution. Most data characterizing genetic variation in different NAFLD phenotypes is derived from case-control association studies involving putative candidate genes. These candidate genes have been selected largely based upon the "two-hit hypothesis" of the pathogenesis of NAFLD, although other hypothesis-independent approaches can also be informative in gene selection. Thus far, candidate gene association studies have had significant limitations such as small cohort sizes and poor reproducibility. Rapid technologic developments are increasing the capability of detecting genetic variation. Identification of the genetic contribution to NAFLD will inform theories of disease pathogenesis and progression and ultimately improve management.

Fatty Liver↗

PubMed2004

Stability in negotiation games and the emergence of cooperation.

Consider a two-player game in which each player contributes a costly resource to the common good of the pair. For such contests, the Nash equilibrium contribution, x*, is one for which neither player can increase its pay-off by unilaterally altering its contribution from x*. We study an elaboration of this game, which allows the players to exchange x-offers back and forth in a negotiation phase until they converge to a final pair of contributions, x1 and x2. A significant feature of such negotiation games, hitherto unrecognized, is the existence of a set of neutrally stable equilibrium points in negotiation phase space. To explore the long-term evolutionary outcome of such games, we simulate populations containing various mixtures of negotiation strategies and, contrary to previous results, we often find convergence to a contribution that is more cooperative than the Nash equilibrium. Mathematical analysis suggests why this might be happening, and provides a novel and robust explanation for cooperation, that negotiation can facilitate the evolution of cooperative behaviour.

Biological Evolution↗

PubMed1984

The nature of the interaction of the P1 recombinase Cre with the recombining site loxP.

The experiments reported here begin to define the molecular nature of the Cre-loxP interaction. It is instructive to compare some of the features of this system with the two other well-characterized site-specific recombination systems of phage lambda and transposon Tn3. In terms of the DNA required for a functional recombining site, the Cre-loxP system appears to be the simplest of the three, requiring only 34 bp of sequence to bind the recombinase. In contrast, both lambda and Tn3 systems have multiple binding sites for their respective recombinases (Hsu et al. 1980; Grindley et al. 1982). It is believed that these additional binding sites, although not the sites of cleavage and strand exchange, are somehow important in bringing the DNA into a suitable configuration necessary for recombination (Better et al. 1982; Grindley et al. 1982; Pollock and Nash 1983). DNA conformation, i.e., whether the DNA substrate is supercoiled or linear, also appears to play a more important role in both of these systems, whereas the Cre-loxP system works efficiently, irrespective of the DNA conformation. All of the recombinases mentioned above create staggered cuts in the DNA during the process of strand exchange and form a covalent attachment to the DNA at the site of cleavage (Reed and Grindley 1981; Craig and Nash 1983b; R.H. Hoess and K. Abremski, in prep.). It should be pointed out that covalent attachment to the DNA is a general feature that these recombinases share with topoisomerases (Gellert 1981). The nature of the cuts made in the DNA is more similar for Int and Cre than for Tn3 resolvase.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

PubMed2002

Coevolutionary games on networks.

We study agents on a network playing an iterated Prisoner's dilemma against their neighbors. The resulting spatially extended coevolutionary game exhibits stationary states which are Nash equilibria. After perturbation of these equilibria, avalanches of mutations reestablish a stationary state. Scale-free avalanche distributions are observed that are in accordance with calculations from the Nash equilibria and a confined branching process. The transition from subcritical to critical avalanche dynamics can be traced to a change in the degeneracy of the cooperative macrostate and is observed for many variants of this game.

Journal Article↗

PubMed2006

Stochasticity and evolutionary stability.

In stochastic dynamical systems, different concepts of stability can be obtained in different limits. A particularly interesting example is evolutionary game theory, which is traditionally based on infinite populations, where strict Nash equilibria correspond to stable fixed points that are always evolutionarily stable. However, in finite populations stochastic effects can drive the system away from strict Nash equilibria, which gives rise to a new concept for evolutionary stability. The conventional and the new stability concepts may apparently contradict each other leading to conflicting predictions in large yet finite populations. We show that the two concepts can be derived from the frequency dependent Moran process in different limits. Our results help to determine the appropriate stability concept in large finite populations. The general validity of our findings is demonstrated showing that the same results are valid employing vastly different co-evolutionary processes.

Biological Evolution↗

PubMed2004

Role of polymerase chain reaction and liver biopsy in the evaluation of patients with asymptomatic transaminitis: implications in diagnostic approach.

BACKGROUND AND AIM: Detection of an asymptomatic rise in the hepatic aminotransferase (ARHA) value has become a distinct and frequent clinical problem. We evaluated a three-step diagnostic algorithm in such patients for maximum yield. METHODS: Consecutive patients with an ARHA value 1.5-fold the upper limit of normal for at least 4 weeks and who were apparently healthy were included in the study. Each patient underwent standard biochemical investigations and a stepwise investigative protocol. In the first step, serological markers for hepatitis viruses, serum ferritin, 24-h urinary copper, alpha-1-antitrypsin phenotyping, and autoimmune markers were carried out. In step two, patients who tested negative for all the above markers had polymerase chain reaction (PCR) analysis for hepatitis B virus (HBV)-DNA and hepatitis C virus (HCV)-RNA. Patients without a diagnosis despite the above investigations underwent a liver biopsy as part of step three. RESULTS: Of 105 patients with ARHA, 38 were excluded for various reasons and 67 were included for the final analysis. The mean age was 35.11 +/- 11.96 years and 56 patients were men. The mean body mass index was 24.17 +/- 3.2 kg/m(2). The stepwise diagnostic algorithm achieved a diagnosis in 65/67 (97%) patients. Non-alcoholic steatohepatitis (NASH) and chronic viral hepatitis were the most common diagnoses, in 24 (36%) patients each. Using the diagnostic algorithm a diagnosis was reached in 34% of patients with only serological and biochemical investigations, whereas PCR for HBV and HCV could further detect the presence of active HBV or HCV viremia in 21% (14/97) and a liver biopsy was necessary to establish the diagnosis in 28/67 (42%) patients. CONCLUSIONS: A stepwise diagnostic algorithm in patients with ARHA resulted in an optimal use of PCR and invasive tests such as liver biopsy. Cryptic HBV and HCV infection was frequent among these patients and PCR was necessary in such cases. NASH and chronic viral hepatitis were the most frequent causes of ARHA.

Adolescent↗

PubMed2006

Mitochondrial glutathione: hepatocellular survival-death switch.

Steatohepatitis represents an advanced stage of fatty liver disease that encompasses alcoholic (ASH) and non-alcoholic steatohepatitis (NASH). The progression from steatosis to steatohepatitis is poorly understood. One of the clues to this progression is the sensitization of hepatocytes to oxidative stress and cytokine-induced cell death. Mitochondrial glutathione (mGSH), which plays a central role in the control of mitochondrial reactive oxygen species (ROS) generation, modulates the sensitivity to cell death pathways. Mitochondrial GSH depletion due to alcohol-mediated alteration in mitochondrial membrane dynamics underlies the susceptibility of hepatocytes from alcohol-fed models to tumor necrosis factor (TNF), and in nutritional and genetic models of hepatic steatosis, mGSH depletion occurs due to the enrichment of mitochondria in free cholesterol, resulting in decreased mitochondrial membrane fluidity. The signaling of TNF through its membrane receptor TNFR1 from complex I to complex II is similar in hepatocytes depleted or not depleted in mGSH, yet hepatocellular susceptibility to TNF occurs if mGSH is depleted. Thus, mGSH is a critical factor in the development of steatohepatitis through sensitization of hepatocytes to inflammatory cytokines, and understanding the homeostasis of cholesterol and its trafficking to mitochondria may be of relevance in the pathophysiology of ASH and NASH.

Apoptosis↗

PubMed2006

Quantitative trait loci analysis of mice administered the methionine-choline deficient dietary model of experimental steatohepatitis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a common disease with a poorly understood etiology, and the methionine-choline-deficient (MCD) diet is a nutritional model of NASH. Quantitative trait loci (QTL) analysis is a standard method for chromosomal mapping of polygenic disease traits. The purpose of this study is to administer mice an MCD diet in order to determine the strain-specific susceptibility for developing steatohepatitis, and to apply a computational methodology of QTL analysis to identify associated chromosomal susceptibility loci. METHODS: Inbred mice were fed an MCD diet and alanine aminotransferase (ALT), hepatic triglycerides, liver weight, and weight loss were measured as phenotypic markers of steatohepatitis. RESULTS: A/J mice developed the highest ALT and hepatic triglyceride levels. Using linear regression analysis, gene loci affecting serum ALT levels were identified on four chromosomes, and four loci that affect liver weight were also identified. In contrast, no QTLs for hepatic triglycerides or body weight were identified. Of note, loci for ALT and liver weight co-localized to proximal segments of chromosomes 2 and 15, in regions previously identified as QTLs for liver fibrosis. CONCLUSIONS: These data indicate that experimental steatohepatitis is a polygenic disease with genes determining ALT, liver weight, and liver fibrosis.

Animals↗

PubMed2005

Increased acylation stimulating protein concentrations in nonalcoholic fatty liver disease are associated with insulin resistance.

OBJECTIVES: As acylation stimulating protein (ASP) acts on adipocytes mainly as a paracrine factor to increase triglyceride synthesis and storage; hypothetically, it may play a similar role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). METHODS: Forty-six male patients with NAFLD (group A), age-matched 30 male patients with chronic viral hepatitis (group B) and 30 age-matched and body mass index (BMI)-matched healthy male subjects were enrolled in the study. RESULTS: Among the NAFLD patients, 10 patients (24.4%) had simple steatosis and 36 patients (69.6%) had nonalcoholic steatohepatitis (NASH). The mean levels of ASP, complement 3, insulin, C-peptide, HOMA-IR, triglyceride, and very low-density lipoprotein (VLDL) were significantly higher in group A patients than both controls and group B. ASP levels correlated significantly in a positive manner with BMI, insulin, and HOMA-IR. CONCLUSIONS: Dysregulation of the ASP pathway may have important metabolic consequences in NASH and is associated with insulin resistance.

Adipocytes↗

PubMed1989

Cancer knowledge and related practices: results from the National Adolescent Student Health Survey.

The National Adolescent Student Health Survey (NASHS) provides information on student knowledge, attitudes, and self-reported practices of eighth and 10th grade students in eight health areas. Data from the NASHS were reviewed relative to cancer risk factors, specifically, smoking, smokeless tobacco use, and nutrition. About 21% of 10th grade students reported smoking and a large percentage of both eighth and 10th grade students reported eating foods high in fat. The data indicate youth may be at increased risk for cancer and that much of that risk can be reduced by eliminating smoking and lowering dietary fat.

Adolescent↗

PubMed1999

Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells.

B cells have previously been identified as the major hematopoietic cell type harboring latent gammaherpesvirus 68 (gammaHV68) (N. P. Sunil-Chandra, S. Efstathiou, and A. A. Nash, J. Gen. Virol. 73:3275-3279, 1992). However, we have shown that gammaHV68 efficiently establishes latency in B-cell-deficient mice (K. E. Weck, M. L. Barkon, L. I. Yoo, S. H. Speck, and H. W. Virgin, J. Virol. 70:6775-6780, 1996), demonstrating that B cells are not required for gammaHV68 latency. To understand this dichotomy, we determined whether hematopoietic cell types, in addition to B cells, carry latent gammaHV68. We observed a high frequency of cells that reactivate latent gammaHV68 in peritoneal exudate cells (PECs) derived from both B-cell-deficient and normal C57BL/6 mice. PECs were composed primarily of macrophages in B-cell-deficient mice and of macrophages plus B cells in normal C57BL/6 mice. To determine which cells in PECs from C57BL/6 mice carry latent gammaHV68, we developed a limiting-dilution PCR assay to quantitate the frequency of cells carrying the gammaHV68 genome in fluorescence-activated cell sorter-purified cell populations. We also quantitated the contribution of individual cell populations to the total frequency of cells carrying latent gammaHV68. At early times after infection, the frequency of PECs that reactivated gammaHV68 correlated very closely with the frequency of PECs carrying the gammaHV68 genome, validating measurement of the frequency of viral-genome-positive cells as a measure of latency in this cell population. F4/80-positive macrophage-enriched, lymphocyte-depleted PECs harbored most of the gammaHV68 genome and efficiently reactivated gammaHV68, while CD19-positive, B-cell-enriched PECs harbored about a 10-fold lower frequency of gammaHV68 genome-positive cells. CD4-positive, T-cell-enriched PECs contained only a very low frequency of gammaHV68 genome-positive cells, consistent with previous analyses indicating that T cells are not a reservoir for gammaHV68 latency (N. P. Sunil-Chandra, S. Efstathiou, and A. A. Nash, J. Gen. Virol. 73:3275-3279, 1992). Since macrophages are bone marrow derived, we determined whether elicitation of a large inflammatory response in the peritoneum would recruit additional latent cells into the peritoneum. Thioglycolate inoculation increased the total number of PECs by about 20-fold but did not affect the frequency of cells that reactivate gammaHV68, consistent with a bone marrow reservoir for latent gammaHV68. These experiments demonstrate gammaHV68 latency in two different hematopoietic cell types, F4/80-positive macrophages and CD19-positive B cells, and argue for a bone marrow reservoir for latent gammaHV68.

Animals↗

PubMed2004

A tale of two sisters.

Hereditary haemochromatosis is the most common inherited disorder in white populations, whereas non-alcoholic steatohepatitis (NASH) is becoming the most common reason for referral for investigation of abnormal liver function tests (LFTs). This report describes two sisters, from similar environments, who were referred to the clinic after being found to be C282Y homozygotes and to have abnormal LFTs. One sister had developed features of haemochromatosis and the other had developed NASH. These cases illustrate the potential non-penetrance of HFE gene mutations and the need to investigate abnormal LFTs fully, even when there is a positive genetic test at the outset.

Diabetes Mellitus, Type 2↗

PubMed2001

Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress.

Oxidative stress is present in the liver of humans with steatosis and nonalcoholic steatohepatitis (NASH) and is a plausible mediator of cellular injury, inflammatory recruitment, and fibrogenesis. CYPs 2E1 and 4A are the microsomal oxidases involved with fatty acid oxidation. Both enzymes can reduce molecular oxygen to produce prooxidant species, which, if not countered efficiently by antioxidants, create oxidative stress. In this theme article, we present the evidence that, in the context of hepatic steatosis, CYPs 2E1 and 4A could generate the "second hit" of cellular injury, particularly when antioxidant reserves are depleted, and propose ways in which this could contribute to the pathogenesis of NASH.

Animals↗

PubMed1997

A proposed nomenclature of the domestic cat karyotype.

High-resolution G- and Q-band patterns of cat (Felis catus) prometaphase chromosomes with more than 450 numbered bands are presented. This number represents approximately twice the number of bands per haploid set exhibited by feline chromosomes at mid-metaphase. A diagrammatic representation of G-banded cat chromosomes has already been described (O'Brien and Nash, 1982); however, precise numbering of bands and landmarks, as in the human karyotype and in the karyotypes of other domestic and laboratory animals, has not yet been available for the domestic cat karyotype, except for the RBG-banded ideograms constructed by Shibasaki et al. (1987) and Rønne and Storm (1995). In this report, we propose a numbering system for the G-banded ideogram reported previously (O'Brien and Nash, 1982) and an extended ideogram at the high-resolution level (473 numbered bands) as a contribution to the future standardization of the feline karyotype.

Animals↗

PubMed2005

Changes in liver histology accompanying massive weight loss after gastroplasty for morbid obesity.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is common in morbid obesity. Our goal was to evaluate the alterations in liver histology and biochemistry before and after weight loss in 51 morbidly obese patients following Mason's vertical banded gastroplasty. METHODS: Two biopsies were performed (on entry and after an average of 18 months), while 16 of these subjects had a third biopsy 17 months after the second. RESULTS: On entry, steatosis and steatohepatitis (mostly grade 3) were present in 98.0% and fibrosis (mostly stage 2) in 94.1% of the subjects. After an excess weight loss of 66%, steatosis and steatohepatitis improved significantly (P<0.001). Although a significant overall decrease in fibrosis occurred (P=0.002), 21 patients (41.1%) did not change and only 6 patients (11.7%) increased in fibrosis. None developed cirrhosis. The decrease in steatohepatitis was significantly correlated (P=0.011) with the reduction of BMI. Fasting serum glucose, lipids, lipoproteins, transaminases, gamma-glutamyl transpeptidase, alkaline phosphatase and fibrinogen were also significantly improved at the time of the second biopsy. The third biopsy performed in 16 of the subjects showed further significant improvement in liver histology. CONCLUSION: NASH improved significantly with massive weight loss in non-diabetic, non-alcoholic, morbidly obese subjects, while fibrosis improved in nearly half of the patients.

Biopsy↗

PubMed2006

Gene expression of leptin, resistin, and adiponectin in the white adipose tissue of obese patients with non-alcoholic fatty liver disease and insulin resistance.

BACKGROUND: Adipose tissue is an active endocrine organ that secretes a variety of metabolically important substances including adipokines. These factors affect insulin sensitivity and may represent a link between obesity, insulin resistance, type 2 diabetes (DM), and nonalcoholic fatty liver disease (NAFLD). This study uses real-time polymerase chain reaction (PCR) quantification of mRNAs encoding adiponectin, leptin, and resistin on snap-frozen samples of intra-abdominal adipose tissue of morbidly obese patients undergoing bariatric surgery. METHODS: Morbidly obese patients undergoing bariatric surgery were studied. Patients were classified into two groups: Group A (with insulin resistance) (N=11; glucose 149.84 +/- 40.56 mg/dL; serum insulin 8.28 +/- 3.52 microU/mL), and Group B (without insulin resistance) (N=10; glucose 102.2 +/- 8.43 mg/dL; serum insulin 3.431 +/- 1.162 microU/mL). RESULTS: Adiponectin mRNA in intra-abdominal adipose tissue and serum adiponectin levels were significantly lower in Group A compared to Group B patients (P<0.016 and P<0.03, respectively). Although serum resistin was higher in Group A than in Group B patients (P<0.005), resistin gene expression was not different between the two groups. Finally, for leptin, neither serum level nor gene expression was different between the two groups. Serum adiponectin level was the only predictor of nonalcoholic steatohepatitis (NASH) in this study (P=0.024). CONCLUSIONS: Obese patients with insulin resistance have decreased serum adiponectin and increased serum resistin. Additionally, adiponectin gene expression is also decreased in the adipose tissue of these patients. This low level of adiponectin expression may predispose patients to the progressive form of NAFLD or NASH.

Adult↗