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Acanthopanax senticosus reverses fatty liver disease and hyperglycemia in ob/ob mice.

Non-alcoholic fatty liver disease (NAFLD) is common in obesity. However, weight reduction alone does not prevent the progression of NAFLD to end-stage disease associated with the development of cirrhosis and liver disease. In a previous experiment, 50% ethanol extract of Acanthopanax senticosus stem bark (ASSB) was found to reduce body weight and insulin resistance in high fat diet-induced hyperglycemic and hyperlipidemic ICR mice. To evaluate the anti-steatosis action of ASSB, insulin-resistant ob/ob mice with fatty livers were treated with ASSB ethanol extract for an 8 week-period. ASSB ethanol extract reversed the hepatomegaly, as evident in reduction of % liver weight/body weight ratio. ASSB ethanol extract also specifically lowered circulating glucose and lipids, and enhanced insulin action in the liver. These changes culminated in inhibition of triglyceride synthesis in non-adipose tissues including liver and skeletal muscle. Gene expression studies confirmed reductions in glucose 6-phosphatase and lipogenic enzymes in the liver. These results demonstrate that ASSB ethanol extract is an effective treatment for insulin resistance and hepatic steatosis in ob/ob mice by decreasing hepatic lipid synthesis.

Animals↗

Proton chemical shift imaging: an evaluation of its clinical potential using an in vivo fatty liver model.

The potential laboratory and clinical utility of proton chemical shift imaging (PCSI) was evaluated by studying fatty liver change in rats, which offered a simple animal model for tissue lipid buildup. There was excellent correlation between lipid group signal intensities from in vivo PCSI studies and liver triglyceride levels obtained from in vitro measurements (R = 0.97). The in vivo T1 relaxation time measurements in fatty liver tissue demonstrated two distinct populations of nonexchanging protons. We explain the reason for the lack of sensitivity in conventional magnetic resonance (MR) imaging studies of fatty liver change and discuss the implications of our findings for MR imaging studies of other tissues. PCSI promises improved diagnostic sensitivity and specificity in studying a wide range of human pathologic conditions.

Animals↗

[Establishing a rat insulin-resistant fatty liver model].

OBJECTIVE: To create a rat insulin resistant fatty liver model. METHODS: 14 male Wistar rats were randomly divided into a model and a control group. The model rats were fed a high-fat diet (45% of energy from fat) for 8 weeks, and the control group a standard diet (19% of energy from fat). Insulin sensitivity was measured with glucose infusion rate (GIR) by the euglycermic hyperinsulinemia clamp technique. The aminotransferase, triglyceride (TG), free fatty acid (FFA), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by biochemical methods, and insulin was measured by radioimmunoassay. The histological and ultrastructural changes of all rat livers were scored using light and electron microscopy. RESULTS: Rats fed the high-fat diet developed panlobular macrovesicular steatosis, lobular inflammatory cell infiltration and abnormal mitochondria, whereas those fed the standard diet had normal livers. All model group rats had elevated levels of aminotransferase, TG, FFA, insulin and liver index, and low GIR. In addition, the high-fat diet increased MDA and decreased SOD. CONCLUSION: A fatty liver and insulin resistance model was successfully developed in rats fed a high-fat diet for 8 weeks, which provided a useful experimental tool for elucidating pathogenesis and treatment of fatty liver.

Animals↗

Acute fatty liver of pregnancy in 3 tertiary care centers.

OBJECTIVE: The purpose of this study was to determine the demographics, clinical presentation, and maternal and neonatal outcomes in patients who were diagnosed with acute fatty liver of pregnancy over a 10-year period. STUDY DESIGN: This was a multicenter retrospective study of women with the diagnosis of acute fatty liver of pregnancy. Records were reviewed for symptoms, laboratory findings, clinical course, and maternal and perinatal outcomes. RESULTS: Sixteen cases of acute fatty liver of pregnancy were identified. Three of the 16 cases had multiple gestations (18%). Eleven of the 16 cases were diagnosed in the antepartum period, and 5 cases were diagnosed within 4 days after delivery. Nausea and vomiting were the most common symptoms (75%). There were 2 maternal deaths (12.5%) and 3 fetal deaths (15%). CONCLUSION: We recommend that patients with persistent nausea, vomiting, or epigastric pain in the third trimester receive evaluation of liver enzymes, renal function, and a complete blood count to rule out the diagnosis of acute fatty liver of pregnancy.

Acute Disease↗

Pathogenesis of fatty liver in rats fed a high protein diet without pyridoxine.

Fatty liver induced in rats by a high protein diet without pyridoxine was studied morphologically. The microscopic change was characterized by accumulation of fat in hepatocytes of the centrolobular and midzonal areas. Electron microscopic examination at an early stage showed marked accumulation of small osmiophilic particles in the granular endoplasmic reticulum and vesicles throughout the cytoplasm with similar particles in the spaces of Disse. After 4 weeks, numerous lipid droplets of various sizes were seen in pericanalicular lysosomes in hepatocytes with concomitant increase in the triglyceride level. The droplets gradually formed larger droplets in the cytoplasm. After 8 weeks, myelin figures together with fat droplets were seen in continuity with the endoplasmic reticulum and occasionally crystal clefts were observed within lysosomes of hepatocytes. These findings suggest that development of fatty liver results from impaired lysosomal degradation of lipid.

Animals↗

Binding of lysophosphatidylcholine to the rat liver fatty acid binding protein.

In this study, lysophosphatidylcholine (lysoPC) was shown to bind to a fatty acid binding protein isolated from rat liver. To demonstrate the binding, lysoPC was incorporated into multilamellar liposomes and incubated with protein. For comparison, binding of both lysoPC and fatty acid to liver fatty acid binding protein, albumin, and heart fatty acid binding protein were measured. At conditions where palmitic acid bound to liver fatty acid binding protein and albumin at ligand to protein molar ratios of 2:1 and 5:1, respectively, lysoPC binding occurred at molar ratios of 0.4:1 and 1:1. LysoPC did not bind to heart fatty acid binding protein under conditions where fatty acid bound at a molar ratio of 2:1. Competition experiments between lysoPC and fatty acid to liver fatty acid binding protein indicated separate binding sites for each ligand. An equilibrium dialysis cell was used to demonstrate that liver fatty acid binding protein was capable of transporting lysoPC from liposomes to rat liver microsomes, thereby facilitating its metabolism. These studies suggest that liver fatty acid binding protein may be involved in the intracellular metabolism of lysoPC as well as fatty acids, and that functional differences may exist between rat liver and heart fatty acid binding protein.

Animals↗

Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes.

To elucidate the function of PPARgamma in leptin-deficient mouse (ob/ob) liver, a PPARgamma liver-null mouse on an ob/ob background, ob/ob-PPARgamma(fl/fl)AlbCre(+), was produced using a floxed PPARgamma allele, PPARgamma(fl/fl), and Cre recombinase under control of the albumin promoter (AlbCre). The liver of ob/ob-PPARgamma(fl/fl)AlbCre(+) mice had a deletion of exon 2 and a corresponding loss of full-length PPARgamma mRNA and protein. The PPARgamma-deficient liver in ob/ob mice was smaller and had a dramatically decreased triglyceride (TG) content compared with equivalent mice lacking the AlbCre transgene (ob/ob-PPARgamma(fl/fl)AlbCre(-)). Messenger RNA levels of the hepatic lipogenic genes, fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase-1, were reduced in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice, and the levels of serum TG and FFA in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice were significantly higher than in the control ob/ob-PPARgamma(fl/fl)AlbCre(-) mice. Rosiglitazone treatment exacerbated the fatty liver in ob/ob-PPARgamma(fl/fl)AlbCre(-) mice compared with livers from nonobese Cre(-) mice; there was no effect of rosiglitazone in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice. The deficiency of hepatic PPARgamma further aggravated the severity of diabetes in ob/ob mice due to decreased insulin sensitivity in muscle and fat. These data indicate that hepatic PPARgamma plays a critical role in the regulation of TG content and in the homeostasis of blood glucose and insulin resistance in steatotic diabetic mice.

Animals↗

[Effects of tea polyphennols on hepatic lipase activity in rabbits with fatty liver].

OBJECTIVE: To investigate the relationship between hepatic lipase activity and fatty degeneration of hepatocytes and explore the effects of tea polyphennols (TP) on the changes of hepatic lipase (HL) activity in rabbits with fatty liver. METHODS: According to serum cholesterol and triglyceride (TC) levels, 19 rabbits were divided into fatty liver group (FL, n=6) fed with high cholesterol diet, TP group (n=7) fed with high cholesterol diet and 20mug/g/d tea polyphennols everyday orally, control group (n=6) fed with normal diet. After 8 weeks, the levels of serum TC, HL activity, HL activity and malondildehyde (MDA) in hepatic tissue were detected, and the pathomorphology of hepatic tissue were determined in all rabbits. RESULTS: The fatty degeneration of hepatocyts in FL group was more severe than that in TP and control group. The serum TC level in TP group (16.87 6.58) mmol/L was higher than that (1.11 0.82) mmol/L in control group (t=5.786, p<0.05), but lower than that (28.49 5.99) mmol/L in FL group (t=3.968, p<0.05). The serum low density lipoprotein-cholesterol level in Tp group (5.10 4.19) mmol/L also higher than that (0.71 1.14) mmol/L in control group (t=3.763, p<0.05), but lower than that (12.15 1.95) mmol/L in FL group (t=2.478, p<0.05). The number of positive dots presenting HL activity level in 100 square micron, hepatic tissue in TP group (3.24 0.17) was higher than that (1.76 0.10) in FL group (t=-3.153, p<0.05), but lower than that (4.14 0.05) in control group (t=-2.902, p<0.05). The levels of MDA in hepatic tissue in TP group (44.66 26.18) nmol/mg was significantly lower than that (75.58 29.88) nmol/mg in FL group (t=2.261, p<0.05), but no evidently different from that (43.64 16.95) nmol/mg in control group. The plasma HL activity was no difference among the three groups. CONCLUSION: The HL activity in hepatic tissue with fatty degeneration of hepatocytes was lower than that in normal liver. Tea polyphennols can increase HL activity in hepatic tissue and protect hepatocytes from fatty degeneration.

Animals↗

[Comparative characteristics of 2 morphometric methods of assessing the degree of liver fatty distrophy].

The fat content in the liver of white male Wistar rats was measured over time (1, 2, 4, 8 and 14 days) after a single exposure to CCl4 within a wide concentration range (from 30 to 25700 mg/m3) by the two morphometric techniques: subjective-graduation and semi-automatic evaluation of the volumetric fat fraction, using a TAS unit (Leitz-Wetzlar). The results obtained with both the methods indicate that the CCl4 concentration equal to 260 mg/m3 is the threshold one as shown by the morphological signs of liver fatty dystrophy. The semi-automatic method offered enables an objective evaluation of the findings, making the research time shorter. To obtain adequate results with the method, it is necessary to observe the rules of the morphological material treatment (contrast selective color, uniform and sufficient thickness of the sections).

Animals↗

Mechanisms of disease: adipocytokines and visceral adipose tissue--emerging role in nonalcoholic fatty liver disease.

There is increasing evidence that visceral adipose tissue is a causative risk factor for fatty liver and nonalcoholic steatohepatitis. Adipose tissue-derived secretory proteins are collectively named adipocytokines. Obesity and mainly visceral fat accumulation impair adipocyte function and adipocytokine secretion and the altered release of these proteins contributes to hypertension, impaired fibrinolysis and insulin resistance. This review summarizes recent findings on the role of the adipocytokines adiponectin, leptin and resistin in the context of hepatic insulin resistance, fatty liver and liver fibrosis. Elevated levels of resistin antagonize hepatic insulin action and raise plasma glucose levels. Leptin exerts insulin-sensitizing effects, but obesity has been linked to leptin resistance and low levels of circulating leptin receptor, indicating that high levels of leptin cannot mediate its beneficial effects. Adiponectin improves insulin sensitivity; however, low circulating adiponectin is found in the obese state. Adiponectin is an anti-inflammatory protein, whereas leptin augments inflammation and fibrogenesis. Disturbed adipocytokine secretion might, therefore, promote hepatic steatosis and the development of nonalcoholic steatohepatitis. The beneficial effects of the therapeutic approaches so far tested in the treatment of fatty liver disease and fibrosis might be due to the modulation of these adipocytokines.

Adipocytes↗

Serum laminin, type IV collagen and hyaluronan as fibrosis markers in non-alcoholic fatty liver disease.

Hepatic fibrosis in patients with non-alcoholic fatty liver disease is associated with progression of the disease. In the present study, we analyzed the discriminative ability of serum laminin, type IV collagen and hyaluronan levels to predict the presence of fibrosis in these patients. In this preliminary report, we studied 30 overweight patients divided into two groups according to the absence (group I, N = 19) or presence (group II, N = 11) of fibrosis in a liver biopsy. Triglycerides, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidade, hyaluronan (noncompetitive fluoroassay), type IV collagen, and laminin (ELISA) were determined. Group II presented significantly higher mean laminin, hyaluronan, type IV collagen, and aspartate aminotransferase values, which were due to the correlation between these parameters and the stage of fibrosis in the biopsy (Spearman's correlation coefficient, rS = 0.65, 0.62, 0.53, and 0.49, respectively). Analysis of the ROC curve showed that laminin values >282 ng/ml were those with the best diagnostic performance, with 87% accuracy. Association of laminin with type IV collagen showed improvement in the positive predictive value (100%), but with reduction in diagnostic sensitivity (64%). When compared with the criteria of Ratziu et al. for the diagnosis of septal fibrosis, laminin values presented a better diagnostic accuracy (83 vs 70%). Determination of extracellular matrix components in serum, especially of laminin, may identify patients with non-alcoholic fatty liver disease and fibrosis and these components may be used as indicators for liver biopsy in these patients.

Adult↗

Prevention of fatty liver and maintenance of systemic valine depletion using a newly developed dual infusion system.

BACKGROUND: Valine-depleted amino acid imbalance, while having a suppressive effect on tumor growth, may induce fatty liver. METHODS: We administered a valine-depleted total parenteral nutrition (TPN) solution by the central venous route to non-tumor-bearing rats and examined the time course of the development of fatty liver. In an attempt to prevent this condition, we administered a continuous infusion of low concentrations of valine via the portal vein simultaneously with administration of central venous valine-depleted nutrition for 4 days. RESULTS: A marked accumulation of triglyceride was observed in the liver on day 4 of the administration of valine-depleted nutrition. It is speculated that such accumulation is the cause of fatty liver. The level of valine in the peripheral blood began to decrease soon after administration was begun and resulted in a state of systemic valine deficiency. Rats given 25% or more of the valine concentration in the standard TPN solution via the portal vein simultaneously with the administration of central venous valine-depleted nutrition, had a triglyceride level similar to that of the control group. The group given 50% or less of the valine concentration had a level of valine in the peripheral blood as low as that of the valine-depleted group, indicating the maintenance of a valine-deficient state. CONCLUSION: Administration of low concentrations of valine via the portal vein simultaneous with central venous administration of valine-depleted TPN solution may prevent fatty liver.

Animals↗

Acute fatty liver of pregnancy -- an underlying condition for herpes simplex type 2 fulminant hepatitis necessitating liver transplantation.

The infrequent occurrence of herpes simplex virus (HSV) hepatitis in healthy women in comparison with the high prevalence of HSV infections suggests that, in addition to deranged immunity, an underlying condition in the liver might be necessary to develop HSV hepatitis. We report the case of a 28-year-old pregnant woman in the 28 (th) week of gestation. Following HSV type 2 infection of the uterine cervix, acute liver failure developed, necessitating urgent liver transplantation. In addition to fulminant HSV type 2 hepatitis, the explanted liver also showed the histological features of acute fatty liver of pregnancy. The presented case suggests a possible pathogenetic role of acute fatty liver of pregnancy in the development of fulminant HSV hepatitis following recurrent infection with HSV in healthy pregnant women. We believe that early histopathological diagnosis, followed by specific antiviral treatment and liver transplantation in selected patients may improve the clinical outcome of otherwise almost uniformly fatal HSV hepatitis.

Adult↗

Impaired hepatic release of triglycerides: a possible cause of acute alcoholic fatty liver in the Rhesus monkey.

1. The mechanism of development of acute alcoholic fatty liver in the Rhesus monkey was investigated by studying the effect of Triton WR-1339 on plasma triglycerides. 2. After ethanol infusion, the rise in plasma triglyceride produced by Triton was greatly reduced and there was an accumulation of triglyceride in the liver. 3. Thus findings suggest that acute alcoholic fatty liver in Rhesus monkeys is probably due to a defect in the release of triglyceride from the liver.

Alcoholism↗