BACKGROUND & AIMS: The rs738409 c.444C > G (p.I148M) polymorphism in PNPLA3 is a major factor predisposing to non-alcoholic fatty liver disease. The aim of the study was to clarify the impact of liver and extrahepatic expression of the PNPLA3 p.148M variant on liver graft steatosis after liver transplantation. METHODS: Fat content was assessed in liver biopsies from 176 transplant recipients. During a period of 4 ± 1 years after transplantation, 17 patients developed grade 3 steatosis, 14 patients grade 2 steatosis, 56 patients grade 1 steatosis, and 89 patients grade 0 steatosis. The influence of the recipient and donor rs738409 genotype and clinical and laboratory data on liver fat content were analyzed using ordinal logistic regression. RESULTS: The PNPLA3 rs738409 CC/CG/GG genotype frequencies, respectively, were 0.494/0.449/0.057 in the graft donors and 0.545/0.330/0.125 in the graft recipients. In the multivariate analysis, the presence of the PNPLA3 c.444G allele in donor (OR 1.62; 95%CI 1.12-2.33), post-transplant BMI (OR 1.14; 95%CI 1.07-1.22), diabetes mellitus (OR 1.99; 95%CI 1.22-3.22), and serum triglycerides (OR 1.40; 95%CI 1.11-1.76) were independent risk factors for increased liver graft fat content. CONCLUSIONS: These data indicate that the liver expression of the PNPLA3 p.148M variant confers a genetic predisposition to liver graft steatosis along with nutritional status and diabetes.
- MeSH
- adipozita genetika MeSH
- alografty patologie MeSH
- biopsie MeSH
- dárci tkání MeSH
- diabetes mellitus epidemiologie MeSH
- dospělí MeSH
- genotyp MeSH
- index tělesné hmotnosti MeSH
- játra patologie MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipasa genetika MeSH
- membránové proteiny genetika MeSH
- pooperační komplikace genetika patologie MeSH
- příjemce transplantátu MeSH
- rizikové faktory MeSH
- transplantace jater * MeSH
- triglyceridy krev MeSH
- ztučnělá játra genetika patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
In the last years, autophagy has been revealed as an essential pathway for multiple biological processes and physiological functions. As a catabolic route, autophagy regulation by nutrient availability has been evolutionarily conserved from yeast to mammals. On one hand, autophagy induction by starvation is associated with a significant loss in body weight in mice. Here, we demonstrate that both genetic and pharmacological inhibition of the autophagy process compromise weight loss induced by starvation. Moreover, autophagic potential also impacts on weight gain induced by distinct hypercaloric regimens. Atg4b-deficient mice, which show limited autophagic competence, exhibit a major increase in body weight in response to distinct obesity-associated metabolic challenges. This response is characterized by the presence of larger adipocytes in visceral fat tissue, increased hepatic steatosis, as well as reduced glucose tolerance and attenuated insulin responses. Similarly, autophagy-deficient mice are more vulnerable to experimentally induced type-I diabetes, showing an increased susceptibility to acute streptozotocin administration. Notably, pharmacological stimulation of autophagy in wild-type mice by spermidine reduced both weight gain and obesity-associated alterations upon hypercaloric regimens. Altogether, these results indicate that systemic autophagic activity influences the resilience of the organism to weight gain induced by high-calorie diets, as well as to the obesity-associated features of both type-1 and type-2 diabetes.
- MeSH
- autofagie * MeSH
- beta-buňky metabolismus patologie MeSH
- buněčná smrt účinky léků genetika MeSH
- cysteinové endopeptidasy nedostatek MeSH
- dieta škodlivé účinky MeSH
- experimentální diabetes mellitus genetika metabolismus patologie MeSH
- myši knockoutované MeSH
- myši MeSH
- obezita chemicky indukované genetika metabolismus patologie MeSH
- proteiny spojené s autofagií nedostatek MeSH
- tukové buňky metabolismus patologie MeSH
- ztučnělá játra chemicky indukované genetika metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Obesity promotes insulin resistance associated with liver inflammation, elevated glucose production, and type 2 diabetes. Although insulin resistance is attenuated in genetic mouse models that suppress systemic inflammation, it is not clear whether local resident macrophages in liver, denoted Kupffer cells (KCs), directly contribute to this syndrome. We addressed this question by selectively silencing the expression of the master regulator of inflammation, NF-κB, in KCs in obese mice. We used glucan-encapsulated small interfering RNA particles (GeRPs) that selectively silence gene expression in macrophages in vivo. Following intravenous injections, GeRPs containing siRNA against p65 of the NF-κB complex caused loss of NF-κB p65 expression in KCs without disrupting NF-κB in hepatocytes or macrophages in other tissues. Silencing of NF-κB expression in KCs in obese mice decreased cytokine secretion and improved insulin sensitivity and glucose tolerance without affecting hepatic lipid accumulation. Importantly, GeRPs had no detectable toxic effect. Thus, KCs are key contributors to hepatic insulin resistance in obesity and a potential therapeutic target for metabolic disease.
- MeSH
- cytokiny metabolismus MeSH
- glukózový toleranční test MeSH
- injekce intravenózní MeSH
- inzulinová rezistence fyziologie MeSH
- Kupfferovy buňky metabolismus patologie MeSH
- lidé MeSH
- malá interferující RNA aplikace a dávkování genetika MeSH
- metabolismus lipidů MeSH
- myši inbrední C57BL MeSH
- myši obézní MeSH
- myši MeSH
- obezita genetika metabolismus patologie MeSH
- systémy cílené aplikace léků MeSH
- techniky in vitro MeSH
- transkripční faktor RelA antagonisté a inhibitory genetika MeSH
- umlčování genů MeSH
- ztučnělá játra genetika metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Non-alcoholic steatohepatitis (NASH), an under- recognized hepatic ailment with increasing prevalence, is fast emerging as the dark horse of hepatic related morbidity and mortality. Though introduced as a hepatic condition as early as 1980, detailed exploration of its causes, underlying mechanisms and therapeutics has largely remained an ignored or neglected field. Only recently, the focus of attention has gravitated towards an understanding of NASH as a pathological manifestation of significance and a search for possible therapeutic interventions. Treatment schedules as of now involve life style management and usage of anti-diabetic or anti-obesity drugs and antioxidants. In the present review, we have focused on the available treatment schedules including herbal agents, plant extracts, polyherbal formulations and isolated phytocompounds. We present here a review of the available literature on pre-clinical and clinical evaluations of herbals including our recent findings on two plant extracts which can be used in mitigating NASH. This review attempts to provide a comprehensive account of NASH and the future of therapeutics and remediation by herbal principles, an aspect of the urgent need to target this important medical condition that contributes to many cases of silent morbidity and mortality.
- MeSH
- antioxidancia terapeutické užití MeSH
- biopsie MeSH
- diagnostické techniky a postupy MeSH
- financování organizované MeSH
- fytoterapie metody MeSH
- játra účinky léků MeSH
- léčivé rostliny MeSH
- lidé MeSH
- obezita komplikace MeSH
- ochranné látky terapeutické užití MeSH
- oxidační stres účinky léků MeSH
- rostlinné extrakty terapeutické užití MeSH
- rostlinné přípravky terapeutické užití MeSH
- ztučnělá játra epidemiologie etiologie genetika terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
The results of study of 53 patients with NAFLD were presented in the article. It was revealed the association of SNPs in the gene PNPLA3 rs738409 with the development of NAFLD in patients of Uzbek nationality. It also provides reliable pathogenetic link the risk allele G with the progression of NAFLD. For patients with NAFLD and G allele is usefully to addition pentoxifylline on the background of the basic therapy.
- MeSH
- biochemická analýza krve MeSH
- dospělí MeSH
- endotel patologie MeSH
- jednonukleotidový polymorfismus MeSH
- kyselina ursodeoxycholová terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ztučnělá játra * genetika patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- MeSH
- dieta MeSH
- dietoterapie MeSH
- fytosteroly farmakologie terapeutické užití MeSH
- hypertriglyceridemie dietoterapie etiologie genetika metabolismus MeSH
- hypolipidemika farmakologie terapeutické užití MeSH
- lidé MeSH
- metaanalýza jako téma MeSH
- metabolismus lipidů MeSH
- rizikové faktory MeSH
- triglyceridy metabolismus MeSH
- ztučnělá játra dietoterapie etiologie genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- úvodní články MeSH
The objective of this work was to study the mechanism of liver parenchyma development under the influence of restriction of diet. Useful information is presented about the pathologic features associated with diet restriction in a chicken animal model of NAFLD. There were 96 chickens of two genotypes, Ross 308 and Cobb 500, in the experiment. The control group was fed a standard mixture ad libitum (ADL). The first experimental group, under restriction from the age of 2 weeks, was fed 80% ADL. The second experimental group was fed 65% ADL from the age of 2 weeks. There were 16 animals in each group. The experiment lasted 5 weeks. Liver parenchyma samples were obtained at the age of 35 days by the necropsy method and then processed by standard histologic methods. The slices were stained by standard staining: hematoxylin-eosin and by Sirius red kit for collagen type I and reticulin visualization. Hepatocyte diameter and the proportion of interstitial tissue to the parenchyma of the liver were measured objectively. Microvesicular liver steatosis was observed after 35 days of restriction. Hepatocyte diameter was significantly influenced by sex, genotype, and the experimental group. The proportion of interstitial tissue to the liver parenchyma was highly influenced by genotype and group, but there were no interactions. An increase in the steatosis histologic grade is associated with inflammatory changes, with decrease of hepatocyte diameter and with a decreasing proportion of interstitial tissue to the liver parenchyma. The results show that early restriction is not associated with the development of fibrosis of the liver tissue.
- MeSH
- experimentální cirhóza jater etiologie genetika patologie patofyziologie MeSH
- fenotyp MeSH
- fyziologie výživy zvířat MeSH
- genotyp MeSH
- hepatocyty patologie MeSH
- hladovění komplikace genetika patologie patofyziologie MeSH
- játra patologie MeSH
- kalorická restrikce MeSH
- kur domácí MeSH
- progrese nemoci MeSH
- sexuální faktory MeSH
- stárnutí MeSH
- věkové faktory MeSH
- velikost buňky MeSH
- ztučnělá játra etiologie genetika patologie patofyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The temporal relationship of hepatic steatosis and changes in liver oxidative stress and fatty acid (FA) composition to the development of non-alcoholic steatohepatitis (NASH) remain to be clearly defined. Recently, we developed an experimental model of hepatic steatosis and NASH, the transgenic spontaneously hypertensive rat (SHR) that overexpresses a dominant positive form of the human SREBP-1a isoform in the liver. These rats are genetically predisposed to hepatic steatosis at a young age that ultimately progresses to NASH in older animals. Young transgenic SHR versus SHR controls exhibited simple hepatic steatosis which was associated with significantly increased hepatic levels of oxidative stress markers, conjugated dienes, and TBARS, with decreased levels of antioxidative enzymes and glutathione and lower concentrations of plasma alpha- and gamma-tocopherol. Transgenic rats exhibited increased plasma levels of saturated FA, decreased levels of n-3 and n-6 polyunsaturated FA (PUFA), and increased n-6/n-3 PUFA ratios. These results are consistent with the hypothesis that excess fat accumulation in the liver in association with increased oxidative stress and disturbances in the metabolism of saturated and unsaturated fatty acids may precede and contribute to the primary pathogenesis of NASH.
- MeSH
- genetická predispozice k nemoci MeSH
- játra metabolismus patologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- nenasycené mastné kyseliny metabolismus MeSH
- oxidační stres MeSH
- potkani inbrední SHR MeSH
- potkani transgenní MeSH
- protein SREBP1 genetika metabolismus MeSH
- ztučnělá játra genetika metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Prague hereditary hypercholesterolemic (PHHC) rat - rat strain crossbred from Wistar rats - is a model of hypercholesterolemia induced by dietary cholesterol. Importantly, no bile salts and/or antithyroid drugs need to be added to the diet together with cholesterol to induce hypercholesterolemia. PHHC rats have only modestly increased cholesterolemia when fed a standard chow and develop hypercholesterolemia exceeding 5 mmol/l on 2 % cholesterol diet. Most of the cholesterol in hypercholesterolemic PHHC rats is found in VLDL that become enriched with cholesterol (VLDL-C/VLDL-TG ratio > 1.0). Concurrently, both IDL and LDL concentrations rise without any increase in HDL. PHHC rats do not markedly differ from Wistar rats in the activities of enzymes involved in intravascular remodelation of lipoproteins (lipoprotein and hepatic lipases and lecithin:cholesterol acyltransferase), LDL catabolism, cholesterol turnover rate and absorption of dietary cholesterol. The feeding rats with cholesterol diet results in development of fatty liver in spite of suppression of cholesterol synthesis. However, even though cholesterolemia in PHHC rats is comparable to human hypercholesterolemia, the PHHC rats do not develop atherosclerosis even after 6 months on 2 % cholesterol diet. Importantly, the crossbreeding experiments documented that hypercholesterolemia of PHHC rats is polygenic. To identify the genes that may be involved in pathogenesis of hypercholesterolemia in this strain, the studies of microarray gene expression in the liver of PHHC rats are currently in progress.
- MeSH
- ateroskleróza genetika metabolismus patologie MeSH
- cholesterol dietní škodlivé účinky MeSH
- cholesterol krev MeSH
- fenotyp MeSH
- financování organizované MeSH
- genetická predispozice k nemoci MeSH
- hybridizace genetická MeSH
- hypercholesterolemie genetika krev patologie MeSH
- játra metabolismus patologie MeSH
- krysa rodu rattus MeSH
- lipoproteiny krev MeSH
- modely nemocí na zvířatech MeSH
- multifaktoriální dědičnost MeSH
- potkani Wistar MeSH
- progrese nemoci MeSH
- ztučnělá játra genetika metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
Congenital disorders of glycosylation (CDG) represent an expanding group of inherited diseases. One of them, ALG8 deficiency (CDG Ih), leads to protein N-glycosylation defects caused by malfunction of glucosyltransferase 2 (Dol-P-Glc:Glc1-Man(9)-GlcNAc(2)-P-P-Dol glucosyltransferase) resulting in inefficient addition of the second glucose residue onto lipid-linked oligosaccharides. So far, only five patients have been described with ALG8 deficiency. We present a new patient with neonatal onset. The girl was born at the 29th week of gestation complicated by oligohydramnios. Although the early postnatal adaptation was uneventful (Apgar score 8 and 9 at 5 and 10 min), generalized oedema, multifocal myoclonic seizures, and bleeding due to combined coagulopathy were present from the first day. Diarrhoea progressing to protein-losing enteropathy with ascites and pericardial effusion developed in the third week of life. Pharmacoresistant seizures and cortical, cerebellar and optic nerve atrophy indicated neurological involvement. No symptoms of liver disease except coagulopathy were observed; however, steatofibrosis with cholestasis was found at autopsy. The girl died at the age of 2 months owing to the progressive general oedema, bleeding and cardio-respiratory insufficiency. Molecular analysis revealed two heterozygous mutations in the ALG8 gene: c.139A>C (p.T47P) and the novel mutation c.1090C>T (p.R364X). Conclusion: The prognosis of patients with ALG8 deficiency is unfavourable. The majority of affected children have early onset of the disease with heterogeneous symptoms including multiple organ dysfunction, coagulopathy and protein-losing enteropathy. Neurological impairment is not a general clinical symptom, but it has to be taken into consideration when thinking about ALG8 deficiency.
- MeSH
- fatální výsledek MeSH
- glukosyltransferasy nedostatek genetika MeSH
- heterozygot MeSH
- kojenec MeSH
- lidé MeSH
- missense mutace * MeSH
- mutační analýza DNA MeSH
- mutantní proteiny genetika MeSH
- novorozenec MeSH
- substituce aminokyselin MeSH
- vrozené poruchy glykosylace diagnóza enzymologie genetika MeSH
- ztučnělá játra enzymologie genetika MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- přehledy MeSH