Animals ; Fatty Liver ; etiology ; genetics ; Humans ; Non-alcoholic Fatty Liver Disease ; Risk Factors

In recent years, nonalcoholic fatty liver disease (NAFLD) has increased because of the growing prevalence of obesity and overweight in the pediatric population. It has become the most common form of chronic liver diseases in children and the related research on NAFLD is expanded. The "two-hit" and "multiple hit" hypothesis have been widely accepted, and some research has shown that genetic, diet structure and environmental factors appear to play a crucial role in the development of pediatric NAFLD. Though it is expected by researchers, there is not an available satisfactory noninvasive marker for the diagnosis of this disease. Fortunately, some new non-invasive prediction scores for pediatric NAFLD have been developed. There is currently no established special therapy, and lifestyle intervention should be adequate for most cases of NAFLD in children. This article reviews the advances in the current knowledge and ideas concerning pediatric NAFLD, and discusses the diagnosis, perspective therapies and scoring methods for this disease.
Child ; Humans ; Non-alcoholic Fatty Liver Disease ; diagnosis ; etiology ; genetics ; Polymorphism, Single Nucleotide ; Risk Factors

OBJECTIVESTo explore the changes of hepatic gene expression during the course of nonalcoholic fatty liver disease (NAFLD) development in rats.

METHODSA rat model of NAFLD was developed by feeding the animals a high-fat diet for 24 weeks. Liver tissues of the model rats and the control rats were analyzed at different time points using rat U230A (Affymetrix GeneChip), which covers 15650 genes.

RESULTSCompared with the control rats, the number of genes expressed differently in the model group rats at 4 and 8 weeks was 426 and 540. The up-regulated genes among them were intracellular phosphorylase genes, metabolic enzyme genes, fatty acid binding protein genes, cytochrome P450 genes, cellular transcription and differentiation genes. The down-regulated genes were ionic channel genes, hormone receptor genes, and cytoskeleton genes. At the 12th week, the number of the genes expressed differently was 501, in which 352 were up-regulated genes, including genes related to inflammation and apoptosis such as interleukin and Toll-like receptor 4. At the 16th week, the number of the differently expressed genes was 665, with 430 up-regulated, such as those related to the inflammation and apoptosis genes and collagen I and fibrosis genes, however cell regeneration genes were down-regulated. At the 24th week the number was 663, of which fibroblast growth factor, transforming growth factor and insulin-like growth factor genes were up-regulated. Of all the differently expressed genes, the number of up-regulated genes was 128, including 10 lipogenic genes, 46 metabolic genes, 15 inflammation genes, 10 apoptosis genes, and 16 fibrosis genes; and the down-regulated genes were 52, including 6 hormone receptor genes, 5 cell regeneration genes and 11 electron transport genes.

CONCLUSIONThe changes of the hepatic gene expression of rats fed a fat-rich diet are related to the duration of the feeding, and are correlated with their histopathology in the livers.

Animals ; Dietary Fats ; Fatty Liver ; etiology ; genetics ; Gene Expression Profiling ; Liver ; metabolism ; Oligonucleotide Array Sequence Analysis ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate whether leptin receptor Lys109Arg polymorphism influences non-alcoholic fatty liver disease.

METHODSGenomic DNA samples were extracted from blood of subjects who had received a physical examination. Genotyping was performed using oligonucleotide microarray and these fluorescence labeled PCR-amplified fragments were hybridized to allele-specific oligonucleotide probes. The relevant mutation was confirmed by sequencing analysis.

RESULTSA total of 180 subjects (109 males and 71 females) were included in the study, 117 of them had fatty liver disease and the other 63 had no liver problems and served as healthy controls. There were 144 (80%) subjects with GG genotype (Arg109Arg), 33 (18.3%) with GA genotype (Lys109Arg) and 3 (1.7%) with AA genotype (Lys109Lys). The distribution of leptin receptor Lys109Arg polymorphism had no significant difference (P > 0.05) between the fatty liver disease patients (95GG, 21GA and 1AA) and the healthy control subjects (49GG, 12GA and 2AA). The abdominal wall fat was significantly thicker in AA genotype subjects (4.1+/-0.4) cm than that in GA (2.8+/-0.6) cm and GG genotype subjects (2.7+/-0.7) cm (F = 5.197, P = 0.006). The serum cholesterol levels in AA genotype subjects (5.1+/-0.4) mmol/L was significantly lower than that in AG (25.5+/-6.9) mmol/L and GG genotype (27.2+/-8.4) mmol/L subjects (F = 8.164, P = 0.005). There were no significant differences in age, body mass index, hip circumference, waist circumference, blood pressure (BP), percentage of body fat, blood protein, triglyceride, HDL and fasting blood glucose between AA, GG and GA genotype subjects.

CONCLUSIONLeptin receptor Lys109Arg polymorphism may be involved in the regulation of distribution of abdominal wall fat thickness and cholesterol metabolism. Whether leptin receptor Lys109Arg polymorphism is in any way related to fatty liver disease is still not known.

Adult ; Arginine ; chemistry ; genetics ; Fatty Liver ; etiology ; genetics ; Female ; Genotype ; Humans ; Lysine ; chemistry ; genetics ; Male ; Middle Aged ; Polymorphism, Genetic ; genetics ; Receptors, Cell Surface ; genetics ; Receptors, Leptin

OBJECTIVETo explore liver X receptor alpha (LXR alpha) gene changes and their significance in nonalcoholic fatty liver disease (NAFLD) in rats.

METHODSA rat model of nonalcoholic fatty liver disease was produced with a fatty diet regime (feeding group, FG). Rats fed with normal diet served as controls (CG). The mRNA and protein expressions of LXR alpha in liver tissues were detected by reverse transcription and polymerase chain reaction (RT-PCR) and Western blot.

RESULTSThe concentration of free fatty acid (FFA) in the sera of GF rats started to increase to 0.33 mmol/L after 4 weeks of fat diet feeding, while the FFA of the CG was just 0.24+/-0.03 mmol/L, and the difference was significant (P<0.05). The concentration of ALT and AST in sera of the FG rats started to increase to 75.8 U/L and 138.9 U/L at the 8th week, much higher than those of the CG (P<0.01), and at the 12th week they increased further (P<0.01). Meanwhile, the mRNA and protein expressions of LXR alpha at the 2nd week was significantly increased to 0.62 (P>0.01) and its peak was reached at the 12th week (P<0.01). There was a significant positive correlation between the expression of LXR alpha and the degree of NAFLD.

CONCLUSIONThe changes of LXR alpha gene are closely related to the development of nonalcoholic fatty liver disease.

Animals ; Fatty Liver ; etiology ; metabolism ; pathology ; Gene Expression ; Liver ; metabolism ; pathology ; Liver X Receptors ; Male ; Orphan Nuclear Receptors ; genetics ; metabolism ; Rats ; Rats, Wistar

BACKGROUNDCurrently it is unclear whether lipid accumulation occurs in a particular sequence and its relationship with whole body insulin resistance (IR). This study aimed to answer this question.

METHODSMale Sprague-Dawley (SD) rats were fed on a normal or a high-fat diet for 20 weeks. Serum triglycerides (TG), serum free fatty acids (FFA), fasting plasma glucose (FPG), and liver and skeletal muscle TG were measured. The glucose infusion rate (GIR) and mRNA levels of acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase-1 (CPT-1) in the liver and skeletal muscle were determined at different stages.

RESULTSCompared with rats fed on the normal diet, serum FFA was not significantly increased in rats fed on the high-fat diet until 20 weeks. In contrast, liver TG was significantly increased by the high-fat diet by four weeks (20-fold; P < 0.01), and remained elevated until the end of the study. However, skeletal muscle TG was not significantly increased by the high-fat diet until 20 weeks (10.6-fold; P < 0.01), and neither was the FPG. The GIR was significantly reduced (1.6-fold; P < 0.01) by the high-fat diet after 8 weeks. The mRNA levels of ACC gradually increased over time and CPT-1 decreased over time, in both the liver and skeletal muscle in rats fed the high-fat diet.

CONCLUSIONSLipid accumulation in the liver occurs earlier than lipid accumulation in the skeletal muscle. Fatty liver may be one of the early markers of whole body IR. Changes in the gene expression levels of ACC and CPT-1 may have important roles in the process of IR development.

Acetyl-CoA Carboxylase ; genetics ; Animals ; Blood Glucose ; analysis ; Carnitine O-Palmitoyltransferase ; genetics ; Fatty Acids, Nonesterified ; blood ; Fatty Liver ; etiology ; Insulin Resistance ; Lipid Metabolism ; Liver ; metabolism ; Male ; Muscle, Skeletal ; metabolism ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Triglycerides ; metabolism

OBJECTIVETo investigate differences between hepatic and biliary lipid metabolism and secretion of genetically gallstone-susceptible (C57L) and resistant (AKR) mice and the mechanism of cholesterol gallstone formation.

METHODSThe inbred C57L and AKR mice were fed a lithogenic diet containing 15% fat, 1.25% cholesterol and 0.5% cholic acid for four weeks. Hepatic cholesterol content and secretion rates of biliary lipids, as well as phenotypes of the liver and gallbladder were determined and examined before and after the feeding of the lithogenic diet.

RESULTSBoth before and after ingestion of the lithogenic diet, hepatic secretion rates of all biliary lipids in C57L mice were markedly higher than that of AKR mice (P < 0.05, P < 0.01, respectively), whereas hepatic cholesterol contents of C57L mice were significantly lower than that of AKR mice (P < 0.05). Furthermore, after consumption of the lithogenic diet, the increase in hepatic secretion rate of biliary cholesterol in C57L mice was significantly higher than that in AKR mice (P < 0.01). Cholesterol gallstones formed in C57L mice and fatty livers developed in AKR mice.

CONCLUSIONSBiliary cholesterol hypersecretion is the key pathophysiological defect of gallstone formation, lith genes have effects on biliary cholesterol hypersecretion and susceptibility to cholesterol gallstone formation in C57L mice. Lithogenic bile is formed at the canalicular membrane and precedes the development of cholesterol gallstones. It is most likely that cholesterol and bile acid hyposecretion make the AKR strain susceptible to the development of fatty livers and resistant to gallstone formation.

Animals ; Bile ; metabolism ; Cholelithiasis ; genetics ; metabolism ; Cholesterol ; analysis ; metabolism ; Fatty Liver ; etiology ; Genetic Predisposition to Disease ; Lipid Metabolism ; Liver ; metabolism ; Male ; Mice ; Mice, Inbred AKR ; Mice, Inbred C57BL

Disease Progression ; Fatty Liver ; complications ; genetics ; pathology ; Genotype ; Hepatitis B, Chronic ; complications ; genetics ; pathology ; Hepatitis C, Chronic ; complications ; genetics ; pathology ; Humans ; Liver Cirrhosis ; etiology ; genetics ; pathology ; Polymorphism, Single Nucleotide

OBJECTIVETo investigate the expression of uncoupling protein 2 (UCP2) and its relationship to the content of adenosine triphosphate (ATP) in livers of nonalcoholic fatty liver disease (NAFLD) rats fed a fat-rich diet.

METHODSTo produce a NAFLD model, a fat-rich diet, consisting of 10% lard oil + 2% cholesterol, was given to Sprague-Dawley rats for a period of 8, 12, 16 and 24 weeks. The normal control rats were fed normal diets. The expressions of UCP2 in the liver were detected by immunohistochemistry and semi-quantitative RT-PCR. The content of ATP of liver was measured by fluorometry.

RESULTSSimple fatty livers were observed in the model group after 8 weeks. From 12 week to 24 week, the livers of the model group rats gradually progressed from simple steatohepatitis to steatohepatitis with pericellular fibrosis. Both immunohistochemistry and semi-quantitive RT-PCR suggested the up-regulated expression of UCP2 in these NAFLD rat livers. The hepatic expression of UCP2 mRNA in the model group was increased with time, and peaked in 24 week by 4.2 times compared to the control group ( t = 16.474, P < 0.01). The ATP content of livers was significantly reduced in the model group compared with the control group at 16 weeks [(2.97+/-0.48) x 10(-8) micromol/g vs. (2.25+/-0.55) x 10(-8) micromol/g, t = 2.419, P < 0.05] and 24 weeks [(2.97+/-0.48) x 10(-8) micromol/g vs. (1.99+/-0.66) x 10(-8) micromol/g, t = 3.248, P < 0.01]. Furthermore, there was a negative correlation between the UCP2 mRNA expression and the content of ATP in the livers of the NAFLD group (r = -0.93, P < 0.01).

CONCLUSIONSThe rat model of NAFLD could be replicated sucessfully by feeding a fat-rich diet for 24 weeks, and the mRNA and its protein of UCP2 were expressed un-regulated in livers of NAFLD. The increasing UCP2 might play a role in the reduction of ATP content in livers of the NAFLD rats.

Adenosine Triphosphate ; metabolism ; Animals ; Dietary Fats ; Fatty Liver ; etiology ; metabolism ; Ion Channels ; biosynthesis ; genetics ; Liver ; metabolism ; Male ; Mitochondrial Proteins ; biosynthesis ; genetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Uncoupling Protein 2

BACKGROUNDS/AIMS: There are controversies on the role of iron overload in the mechanism of liver injury in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the prevalence of peripheral iron overload, and to study the presence of HFE mutations (C282Y, H63D, S65C) in a cohort of Korean NAFLD patients. METHODS: 255 patients with NAFLD were included. The patients had been diagnosed as having NAFLD by the criteria of elevated aminotransferase levels, compatible ultrasonographic findings and exclusion of other etiologies. Blood samples were tested for chemistry, iron profile, and mutational analysis for HFE gene (C282Y, H63D, S65C). RESULTS: Of the 255 NAFLD patients, the prevalence of peripheral iron overload was 19.2% according to the cutoff level of transferrin saturation (TS) > 45%, and 3.9% of NAFLD patients were having hyperferritinemia over 400 ng/mL. Hyperferritinemia was significantly associated with elevated serum levels of fasting glucose, AST and TS. We found the presence of H63D mutation, either heterozygote or homozygote, among the NAFLD patients with peripheral iron overload. CONCLUSIONS: The prevalence of peripheral iron overload in the Korean NAFLD patients was not rare, and the presence of H63D mutation among NALFD patients was identified. Further studies on the significance of iron overload or HFE mutation in the pathogenesis of NAFLD are needed.
Adult ; Cohort Studies ; Fatty Liver/*etiology/genetics ; Female ; Heterozygote ; Histocompatibility Antigens Class I/*genetics ; Homozygote ; Humans ; Iron Overload/complications/*epidemiology ; Korea ; Male ; Membrane Proteins/*genetics ; Middle Aged ; Point Mutation ; Prevalence ; Transferrin/metabolism