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PubMed2001

Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a key regulator of lipid homeostasis in hepatocytes and target for fatty acids and hypolipidemic drugs. How these signaling molecules reach the nuclear receptor is not known; however, similarities in ligand specificity suggest the liver fatty acid binding protein (L-FABP) as a possible candidate. In localization studies using laser-scanning microscopy, we show that L-FABP and PPARalpha colocalize in the nucleus of mouse primary hepatocytes. Furthermore, we demonstrate by pull-down assay and immunocoprecipitation that L-FABP interacts directly with PPARalpha. In a cell biological approach with the aid of a mammalian two-hybrid system, we provide evidence that L-FABP interacts with PPARalpha and PPARgamma but not with PPARbeta and retinoid X receptor-alpha by protein-protein contacts. In addition, we demonstrate that the observed interaction of both proteins is independent of ligand binding. Final and quantitative proof for L-FABP mediation was obtained in transactivation assays upon incubation of transiently and stably transfected HepG2 cells with saturated, monounsaturated, and polyunsaturated fatty acids as well as with hypolipidemic drugs. With all ligands applied, we observed strict correlation of PPARalpha and PPARgamma transactivation with intracellular concentrations of L-FABP. This correlation constitutes a nucleus-directed signaling by fatty acids and hypolipidemic drugs where L-FABP acts as a cytosolic gateway for these PPARalpha and PPARgamma agonists. Thus, L-FABP and the respective PPARs could serve as targets for nutrients and drugs to affect expression of PPAR-sensitive genes.

Animals↗
PubMedDate not supplied

[The treatment of acute fatty liver of pregnancy using plasma exchange].

A 33-year-old gravida 6, para 5, developed acute fatty liver of pregnancy at 35 weeks' gestation. This clinical picture was seen after caesarean section and delivery of a healthy infant. Post partum hepatic dystrophy associated with coma hepatica, acute renal failure and disseminated, intravascular coagulation was successfully treated with three large-volume plasmaphereses using FFP exchange plasma in combination with haemodialysis. The patient survived and her liver function was restored to normal.

Acute Kidney Injury↗
PubMed1979

Liver injury and lipid metabolism: sex differences in the fatty liver induced by d-galactosamine.

The time-course of plasma lipid alterations and of triglyceride accumulation in the liver was investigated in male and female rats 12, 24 and 48 hours after treatment with 3.48 mmole/kg (0.75 g/kg) D-galactosamine (Ga1N). In the early stages of Ga1N-induced liver injury the concentrations of triglycerides, phospholipids and total cholesterol decreased, while in the later stages these values in the plasma increased above normal, especially in male animals. In contrast, glucose concentrations continually decreased, while free fatty acid (FFA) levels rose to twice those normal in female animals. Male animals had significantly lower FFA-values throughout the experiment. Consistently, the triglyceride accumulation on liver was 75 mg/g in female animals 24 hours after Ga1N administration, while male animals in the average showed only 33 mg/g triglycerides. Similar fatty infiltrations were obtained in female animals with the rather low doses of 1.16 and 2.32 mmol/kg Ga1N. It is concluded that the increase of FFA-influx after Ga1N administration is the main cause for fatty infiltration, the sex differences in the plasma FFA concentrations explaining the net differences in liver triglyceride accumulation. Additional effects in the pathogenesis of fatty liver might stem from disturbed glycosylation reactions and/or an altered secretion and metabolism of lipoproteins after Ga1N-induced liver injury.

Animals↗
PubMed1996

Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele.

Acute fatty liver of pregnancy (AFLP) is a devastating late gestational complication with many similarities to the inherited disorders of mitochondrial fatty acid oxidation. We report the molecular defects in a woman with AFLP and her infant who subsequently was diagnosed with trifunctional protein (TFP) deficiency. We used single-stranded conformation variance and DNA sequence analyses of the human TFP alpha-subunit gene, which encodes the long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity, to demonstrate a C to T mutation (C1678T) in exon 16 present on one allele in the mother and the affected infant. This creates a premature termination codon (R524Stop) in the LCHAD domain. Using reverse transcriptase-PCR amplification of the alpha-subunit mRNA from cultured fibroblasts, we demonstrated that transcripts containing this R524Stop mutation are present at very low levels, presumably because of rapid mRNA degradation. The affected infant also had the common E474Q mutation (nucleotide G1528C) on the second allele. Thus, he is a compound heterozygote. The father and two normal siblings are heterozygous for this E474Q mutation. This initial delineation of the R524Stop mutation provides evidence of the heterogeneity of genetic defects responsible for TFP deficiency and AFLP.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1984

Acute fatty liver of pregnancy. Survival with early cesarean section.

We have cared for two women with acute fatty liver of pregnancy in the past two years. Both patients survived as did three of babies. This compares with published mortality rates of up to 85% with this condition. Both patients presented with symptoms and signs of impending liver failure during the third trimester of pregnancy. Both patients were jaundiced, had elevated aminotransferases, leukocytosis, hepatic encephalopathy, and disseminated intravascular coagulation. The diagnosis was confirmed by liver biopsy in both. We attribute the unusually good outcome of these women and their children to early recognition of their disorder and prompt delivery once the diagnosis was considered.

Acute Disease↗
PubMed2002

Gestational thrombocytopenia and pregnancy-induced antithrombin deficiency: progenitors to the development of the HELLP syndrome and acute fatty liver of pregnancy.

The syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome) and of acute fatty liver of pregnancy (AFLP) do not have an abrupt onset. Thrombocytopenia or reduced antithrombin activity, or both, seen at presentation do not result from these complications. There are a small number of pregnant women who exhibit a gradual antenatal decline in platelet counts or antithrombin activity, or both, irrespective of the presence or absence of preeclampsia. Those who develop a profound decrease in either platelet counts or antithrombin activity are at an increased risk for developing perinatal aspartate aminotransferase (AST) elevation. Thrombocytopenia or reduced antithrombin activity, or both, precede the onset of these diseases. Therefore, monitoring of platelet counts and antithrombin activity during pregnancy is clinically useful for identifying women at an increased risk of the HELLP syndrome and AFLP. Because women with twin pregnancies are likely to exhibit a decrease in platelet counts or antithrombin activity, or both, compared with women with singleton pregnancies, HELLP syndrome and AFLP are more likely to occur in women with twin pregnancies.

Acute Disease↗
PubMedDate not supplied

Focal fatty liver after pancreaticoduodenectomy: a case report of a rare entity of intrahepatic tumor.

Diffuse fatty degeneration often occurs after pancreaticoduodenectomy due to altered lipid metabolism and nutritional malabsorption. Focal fatty change of the liver is characterized by a well-demarcated region, and the pathogenesis remains unclear. A 60-year-old woman underwent pancreaticoduodenectomy for bile duct cancer 10 years before. During follow-up, an intrahepatic tumor was detected in the lateral segment in the liver. The differential diagnosis included cholangiocarcinoma and metastatic tumor on images of plain computed tomography, ultrasonography, and magnetic resonance angiography. The patient underwent lateral segmentectomy of the liver. The tumor was a soft yellow mass, and histological examination indicated focal fatty liver. It was thought that the fatty liver was caused by localized low blood supply and dysabsorption of lipoprotein after pancreaticoduodenectomy.

Adenocarcinoma↗
PubMed2004

Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity.

Fatty liver is frequent in the apolipoprotein B (apoB)-defective genetic form of familial hypobetalipoproteinemia (FHBL), but interindividual variability in liver fat is large. To explain this, we assessed the roles of metabolic factors in 32 affected family members with apoB-defective FHBL and 33 related and unrelated normolipidemic controls matched for age, sex, and indices of adiposity. Two hour, 75 g oral glucose tests, with measurements of plasma glucose and insulin levels, body mass index, and waist-hip ratios were obtained. Abdominal subcutaneous, intraperitoneal (IPAT), and retroperitoneal adipose tissue masses were quantified by MR imaging, and hepatic fat was quantified by MR spectroscopy. Mean +/- SD liver fat percentage values of FHBL and controls were 14.8 +/- 12.0 and 5.2 +/- 5.9, respectively (P = 0.001). Means for these measures of obesity and insulin action were similar in the two groups. Important determinants of liver fat percentage were FHBL-affected status, IPAT, and area under the curve (AUC) insulin in both groups, but the strongest predictors were IPAT in FHBL (partial R(2) = 0.55, P < 0.0002) and AUC insulin in controls (partial R(2) = 0.59, P = 0.0001). Regression of liver fat percentage on IPAT fat was significantly greater for FHBL than for controls (P < 0.001). In summary, because apoB-defective FHBL imparts heightened susceptibility to liver triglyceride accumulation, increasing IPAT and insulin resistance exert greater liver fat-increasing effects in FHBL.

Adipose Tissue↗
PubMed2006

Increased production of IL-1alpha and TNF-alpha in lipopolysaccharide-stimulated blood from obese patients with non-alcoholic fatty liver disease.

Enhanced pro-inflammatory cytokine production is considered a pathogenic factor in non-alcoholic fatty liver disease (NAFLD). Peripheral blood production of interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) was studied in relation to the severity of histological changes of the liver in obese NAFLD patients. Basal levels in serum and production of IL-1alpha and TNF-alpha in peripheral blood cell cultures after stimulation with lipopolysaccharide (enzyme-linked immunoabsorbent assays) were measured in 11 patients with steatosis and 15 with steatohepatitis, who underwent gastrectomy with a gastro-jejunal anastomosis in roux and Y, and in 9 controls who underwent anti-reflux surgery. Production of IL-1alpha and TNF-alpha was 122 and 67% higher in patients with steatosis than control values, respectively. In patients with steatohepatitis, IL-1alpha production was 300 and 80% higher and that of TNF-alpha 110 and 26% higher, as compared with controls and steatosis patients, respectively. Production of IL-1alpha was positively correlated with that of TNF-alpha (r=0.78, p<0.0001). IL-1alpha and TNF-alpha production were both positively correlated with the degree of steatosis (r=0.68, p<0.001 and r=0.74, p<0.0001) and steatohepatitis (r=0.77 and r=0.75, p<0.0001) at liver biopsy, and with the homeostasis model assessment index (r=0.73, p<0.0001 and r=0.63, p<0.01), respectively. Basal serum IL-1alpha and TNF-alpha levels were comparable in the three groups studied. It is concluded that elevated production of IL-1alpha and TNF-alpha by in vitro stimulated whole blood cell cultures occurs in NAFLD obese patients, which might play a pathophysiological role upon inflammatory leukocyte infiltration of the liver.

Adult↗
PubMed1990

Estrogen induction of fatty liver in dairy cattle.

Two trials were conducted to determine if estrogen contributes to development of fatty liver in dairy cattle. During trial 1, eight late lactation, nonpregnant cows were assigned to 0 or 15 mg estradiol-17 beta benzoate/d treatment. Days 1 to 3 of the trial were for baseline measurements, and treatments were given from d 4 to 21; on d 20 and 21 animals were fasted. Short-term feed deprivation resulted in increased plasma FFA concentrations and rapid accumulation of triglyceride into liver tissue obtained by biopsy. During starvation, plasma FFA concentration and liver triglyceride content were lower for cows receiving the estradiol-17 beta treatment relative to cows receiving control treatment. Very low density lipoprotein concentration in blood increased dramatically in three of four animals during estradiol-17 beta administration. Because of the decrease in milk production during estradiol-17 beta treatment, it was not known whether this represented a decrease in very low density lipoprotein clearance from blood or reflected a lipotropic response to estradiol-17 beta. Therefore, a second trial was conducted employing nonlactating cows, and control and estradiol-17 beta-treated animals were pair fed. The trial was 33 d with d 1 to 3 for baseline measurements, and treatments were administered from d 4 to 33. All animals were starved from d 19 to 23. Estradiol-17 beta increased hepatic lipid and triglyceride accumulation and plasma very low density lipoprotein concentration during starvation. Plasma FFA concentration was also increased by estradiol-17 beta during this time; therefore, a direct or indirect effect of estrogen on hepatic lipid metabolism could not be delineated.

Animals↗
PubMed2005

Influence of metabolic syndrome, viral genotype and antiviral therapy on superimposed fatty liver disease in chronic hepatitis C.

BACKGROUND/AIMS: The prevalence and clinical implications of non-alcoholic fatty liver disease in patients with chronic hepatitis C remain unknown in Taiwan. METHODS: We addressed the relevant issues by analysing 95 naive Taiwanese patients infected with either hepatitis C virus (HCV) genotype 1 (n = 57) or 2 (n = 38), receiving interferon alone (n = 41) or in combination with ribavirin (n=54) therapy. A single pathologist scored steatosis and steatohepatitis at baseline and 24 weeks after antiviral treatment. RESULTS: At baseline, steatosis and steatohepatitis were present in 44 (46%) and four (4%) patients, respectively. Variables associated with steatosis in logistical regression were hyperglycaemia (P = 0.01), hypertriglyceridaemia (P = 004) and body mass index > or = 27 (P = 0.009), but not HCV genotype or viral load. The grade of steatosis correlated well with the number of metabolic syndrome parameters (P = 0.018). Interferon monotherapy, advanced age and HCV genotype 1, but not steatosis, correlated with lower sustained response rate. After treatment, steatosis improved in 19 and worsened in nine, which also did not correlate with HCV genotype (P = 0.850) or sustained response to antiviral therapy (P = 0.246). CONCLUSIONS: Hepatic steatosis in Taiwanese patients with chronic hepatitis C was associated with features of the metabolic syndrome, but did not correlate with HCV genotype, advanced fibrosis or the response to antiviral therapy.

Adult↗
PubMed1982

Limited elastase digestion of pigeon liver fatty acid synthetase with retention of all partial enzyme activities.

Pigeon liver fatty acid synthetase which contains two subunits of 240,000 daltons each has been treated with elastase. This treatment yields four protein fragments which can be separated on sodium dodecyl sulfate (SDS)-gel electrophoresis. After the subunit protein has been treated with elastase, all of the partial enzyme activities catalyzed by the complex are present, but enzyme activity for fatty acid synthesis is lost. The formation of protein fragments during proteolysis has been followed by densitometric scanning of the SDS gels. The results of these scans have suggested that (a) there are two peptide components present in the highest molecular weight band, (b) both are rapidly digested to yield the second and third largest peptides, and (c) a further cleavage of the third largest peptide gives rise to the smallest of the four major peptides. Crossed-rocket immunoelectrophoretic analysis of the four protein fragments has confirmed these conclusions and established also that the three smallest peptides are homogeneous. Each of the four peptides has been isolated by preparative SDS-gel electrophoresis, and antibody to one has been prepared. This antibody fraction immunotitrates overall fatty acid synthetase activity and immunoprecipitates the native enzyme. Immunoelectrophoresis of the four elastase-digested synthetase products against this antibody showed some cross-reactivity with a peptide that was neither the precursor nor the product of the immunogen. This cross-reacting antibody was removed by reaction with the nonrelated protein to yield antibody specific for one region of the fatty acid synthetase complex.

Animals↗
PubMed2005

Review article: non-alcoholic fatty liver disease and hepatitis C--risk factors and clinical implications.

Hepatitis C and non-alcoholic fatty liver disease (NAFLD) are the two most common liver diseases in the Western hemisphere. It is therefore natural that these conditions often co-exist in the same individual. Hepatitis C, especially genotype 3, is often associated with hepatic steatosis. In subjects with genotype 3 infection, a sustained virologic response to treatment is associated with improvement in hepatic steatosis. The diagnosis of NAFLD in a subject with hepatitis C infection is based on the presence of hepatic steatosis. Most investigators require the presence of at least grade II steatosis to warrant a diagnosis of concomitant NAFLD because the significance of minimal steatosis is uncertain. The presence of steatohepatitis is surmised by the additional presence of Mallory bodies, cytologic ballooning and pericellular fibrosis. It is of paramount importance to exclude alcohol as a cause of these histologic findings in this population before a diagnosis of NAFLD is made. The presence of NAFLD in subjects with hepatitis C genotype 1 infection is most strongly associated with the presence of the metabolic syndrome and insulin resistance. The degree of hepatic steatosis correlates with the degree of hepatic fibrosis and the presence of concomitant steatosis is associated with more advanced fibrosis. The presence of cytologic ballooning confers an additional risk for increased fibrosis. Insulin resistance and hyperinsulinemia have been associated with increased collagen production by hepatic stellate cells. Subjects with hepatitis C and NAFLD are more likely to be virologic nonresponders following anti-HCV therapy. The value of treating insulin resistance and NAFLD prior to antiviral therapy remains to be experimentally verified.

Antiviral Agents↗