FATTY ACID FLUX AND TRIGLYCERIDE SECRETION IN THE HYDRAZINE-INDUCED FATTY LIVER.
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Metabolic syndrome from the view point of public health: with special reference to nonalcoholic fatty liver disease.
Changes in human behavior and lifestyle over the last century have resulted in a dramatic increase in the incidence of obesity, type 2 diabetes, and the metabolic syndrome. Differences in the reported overall prevalence of the metabolic syndrome, which is generally in the range of 10-30% depend on the diagnostic criteria and subjects of the study. Recently, Japanese criteria for diagnosis of the metabolic syndrome were defined. With these criteria, presence of visceral obesity is essential for the diagnosis and is simply determined by measurement of waist circumference. Reflecting a dramatic increase in the incidence of obesity and type 2 diabetes, the incidence of the metabolic syndrome is increasing in Japan as well as in Western countries, regardless of the criteria applied. Recently, the number of workers with elevated liver enzymes, in whom virus hepatitis, alcoholic liver disease, drug induced hepatitis, autoimmune hepatitis, and iron overload were ruled out as causal agents, has also be found to be increasing at workplace health checkups. Most of such workers have components of the metabolic syndrome and the presence of steatosis in the liver, this pathologic condition now being termed nonalcoholic fatty liver disease (NAFLD). In this review, we describe the relationship between NAFLD and the metabolic syndrome.
Adult↗
Metabolic basis of diethylaminoethoxyhexestrol-induced phospholipid fatty liver.
Diethylaminoethoxyhexestrol caused a foam cell lipidosis in humans characterized by phospholipid storage in the liver, spleen, and other tissues, and this represents the first description of acquired lipidosis caused by a drug. It has been proposed that diethylaminoethoxyhexestrol causes phospholipid fatty liver by concentrating in lysosomes and inhibiting phospholipases but it has not previously been possible to measure the intralysosomal concentration of diethylaminoethoxyhexestrol. In this paper we report for the first time the intralysosomal concentration of this drug in rats. After a single oral dose of diethylaminoethoxyhexestrol (100 mg/kg) the intralysosomal concentration was 7.9 mM at 2.5 h, 15.6 mM at 12 h, and 20.9 mM at 24 h, respectively. The total phospholipid content of lysosomes in drug-treated rats increased 1.9-, 6.0-, and 7.6-fold over control at 2.5, 12, and 24 h, respectively. Purified lysosomal phospholipase A1 was strongly inhibited by diethylaminoethoxyhexestrol in vitro. In phospholipid fatty liver, phospholipid accumulation in lysosomes appears to be caused by the presence of diethylaminoethoxyhexestrol in lysosomes at concentrations estimated to be 7.9-20 mM, because drug levels above 1 mM completely block the activity of purified lysosomal phospholipase A1 in vitro.
Animals↗
Polyenylphosphatidylcholine attenuates alcohol-induced fatty liver and hyperlipemia in rats.
Chronic administration of a soybean-derived polyenylphosphatidylcholine (PPC) extract prevents the development of cirrhosis in alcohol-fed baboons. To assess whether this phospholipid also affects earlier changes induced by alcohol consumption (such as fatty liver and hyperlipemia), 28 male rat littermates were pair-fed liquid diets containing 36% of energy either as ethanol or as additional carbohydrate for 21 d, and killed 90 min after intragastric administration of the corresponding diets. Half of the rats were given PPC (3 g/l), whereas the other half received the same amount of linoleate (as safflower oil) and choline (as bitartrate salt). PPC did not affect diet or alcohol consumption [15.4 +/- 0.5 G/(kg.d)], but the ethanol-induced hepatomegaly and the hepatic accumulation of lipids (principally triglycerides and cholesterol esters) and proteins were about half those in rats not given PPC. The ethanol-induced postprandial hyperlipemia was lower with PPC than without, despite an enhanced fat absorption and no difference in the level of plasma free fatty acids. The attenuation of fatty liver and hyperlipemia was associated with correction of the ethanol-induced inhibition of mitochondrial oxidation of palmitoyl-1-carnitine and the depression of cytochrome oxidase activity, as well as the increases in activity of serum glutamate dehydrogenase and aminotransferases. Thus, PPC attenuates early manifestations of alcohol toxicity, at least in part, by improving mitochondrial injury. These beneficial effects of PPC at the initial stages of alcoholic liver injury may prevent or delay the progression to more advanced forms of alcoholic liver disease.
Animals↗
Studies on the synthesis of rat liver fatty acid synthetase.
The synthesis of the multienzyme complex rat liver fatty acid synthetase was investigated utilizing modifications of methods developed in the laboratory of Schimke (Schimke, R. T. (1964) J. Biol. Chem. 239, 3808-3817 and Arias, I. M., Doyle, D., and Schimke, R. T. (1969) J. Biol. Chem. 244, 3303-3315). The relative amounts of radioactivity from a pulse of labeled lysine appearing in polypeptides derived from purified synthetase complex can be measured compensating for the varying amounts of lysine per polypeptide chain. The results show that labeled amino acid is incorporated into polypeptides derived from the complex at heterogeneous rates. However, 10 to 15 hours after the administration of a pulse, the amount of label per lysine residue in these polypeptides is identical. The results support the previously proposed model of this multienzyme complex (Tweto, J., Dehlinger, P., and Larrabee, A. R. (1972) Biochem. Biophys. Res. Commun. 48, 1371-1377). The previous work and that reported here suggests the existence of a pool of synthetase subunits which is an obligatory intermediate in both synthesis and turnover of the complex. The results obtained in this work are consistent with this model if the exchange of subunits into the intact complex is a relatively slow process requiring several hours to reach equilibrium.
Animals↗
Liver fatty acid-binding protein: an early and sensitive plasma marker of hepatocellular damage and a reliable predictor of graft viability after liver transplantation from non-heart-beating donors.
OBJECTIVE: Liver fatty acid-binding protein (L-FABP) is a small protein (15 kD) involved in the intracellular transport of long-chain fatty acids in the liver. The L-FABP is regarded as a sensitive marker for liver cell damage. In a pig model for liver transplantation (LTx) from non-heart-beating donors (NHBD), we evaluated plasma changes of L-FABP early after reperfusion of grafts exposed to increasing periods of warm ischemia (WI). METHODS: Porcine livers were procured after 0, 15, 30, 45, and 60 minutes' WI. After 4 hours' cold ischemia (CI), LTx was performed. Primary graft nonfunction (PNF) and day 4 survival were recorded. Plasma samples were collected prior to and 15, 60, and 180 minutes after graft reperfusion for determination of L-FABP and aspartate transaminase (AST). RESULTS: Early after reperfusion, levels of L-FABP correlated well with the duration of WI. The PNF developed in 100% of animals after 60 minutes of WI, 50% after 30, and 45 minutes' WI, and was absent after no WI and 15 minutes of WI. Day 4 survival was 100% in 0 minutes' WI, 83% in 15 minutes' WI, 50% in 30 and 45 minutes' WI, and 0% in 60 minutes of WI. CONCLUSIONS: Plasma levels of L-FABP correlated well with WI and concomitant hepatocellular damage in LTx from NHBD. Monitoring of posttransplant L-FABP plasma levels is a valuable new tool to quantify early the extent of parenchymal cell damage of NHBD livers and to predict their viability and function.
Animals↗
Effects of osmolytes on unfolding of chicken liver fatty acid synthase.
Urea-induced aggregation of chicken liver fatty acid synthase [acyl-CoA:malonyl-CoA C-acyltransferase (decarboxylating, oxoacyl- and enoyl-reducing and thioester-hydrolyzing), EC 2.3.1.85] was studied. The aggregation was facilitated at increased ionic strength. Methyl-beta-cyclodextrin and some osmolytes, such as glycerol, sucrose, proline, glycine, and heparin, could effectively prevent the aggregation, implying an artificial chaperone role of those substances during fatty acid synthase unfolding. The osmolytes also protected the enzyme from inactivation.
Animals↗
The binding of cholesterol and bile salts to recombinant rat liver fatty acid-binding protein.
The physiological role of liver fatty acid-binding protein (L-FABP) has yet to be clarified. An important feature of this member of the family of intracellular lipid-binding proteins is the wide range of compounds that have been identified as potential physiological ligands. By using recombinant L-FABP, the binding of cholesterol, bile salts and their derivatives has been investigated under conditions that allow a direct comparison of the binding affinities of these ligands for fatty acids. The results demonstrate an inability of L-FABP to bind cholesterol, although the anionic derivative, cholesteryl sulphate, will bind under similar assay conditions. Of the bile salts examined, lithocholate and taurolithocholate sulphate showed the greatest binding to L-FABP. It is proposed that an important function of L-FABP is to bind certain physiological amphipathic anions, thus preventing the "free' concentrations of these compounds from exceeding their critical micelle concentration, which could result in cell damage.
Animals↗
Nonalcoholic steatosis and steatohepatitis IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines.
Macrophage products, such as cytokines, prostanoids, nitric oxide, and reactive oxygen intermediates, influence the function and viability of macrophages and neighboring cells. Given that the liver has one of the largest resident macrophage populations in the body, it is not surprising that hepatic macrophages [i.e., Kupffer cells (KC)] are involved in the pathogenesis of many kinds of liver disease. This review summarizes the abnormalities that have been demonstrated in bone marrow, peritoneal and hepatic macrophage of leptin-resistant (fa/fa) rats and leptin-deficient (ob/ob) mice, two animal models for nonalcoholic fatty liver disease (NAFLD). Evidence supports the concept that altered KC function influences the viability of other cells, such as lymphocytes and hepatocytes, in fatty livers, thereby contributing to the pathogenesis of NAFLD in animals with reduced leptin activity. Further work is needed to determine whether KC dysfunction is a component of more generalized mechanisms that lead to NAFLD.
Animals↗
Is malnutrition necessary for the development of alcoholic fatty liver in the rat?
Ingestion of various liquid diets containing 36% calories as ethanol and 35% calories as fat does not provide adequate nutrition to young growing rats. Studies conducted with the aforementioned diets have the effects of malnutrition confounded with those of alcohol administration. Feeding a 26% alcohol liquid diet, which results in adequate nutrient intake with the same level of alcohol ingestion as the 36% alcohol diet, does not result in fatty liver development in the rat. The concept that prevailed for 25 years that fatty liver is caused despite adequate nutrition and hence is due to alcohol alone is therefore erroneous.
Animals↗
Proposal for a histological scoring and grading system for non-alcoholic fatty liver disease.
AIM/BACKGROUND: The spectrum of histopathological features in non-alcoholic fatty liver disease (NAFLD) has been well described. At least two scoring systems have been established. We propose here a system in which numerical scores are obtained using the different features. METHODS: Twenty-five cases of well-defined NAFLD were identified. Two pathologists blinded to identifiers and clinical data independently scored the liver biopsies twice for portal fibrosis (PF: 0-6), lobular inflammation and necrosis (LIN: 0-3), Mallory bodies (MB: 0-3), hepatocyte ballooning (HB: 0-3), perisinusoidal fibrosis (PSF: 0-3) and fatty change (FC: 1-4). The kappa statistic tested observer concordance. Non-parametric measures of correlation and hierarchical cluster analysis were used to elaborate a grading system. RESULTS: A broad spectrum of NAFLD was observed. Intra- and interobserver concordance was satisfactory. An activity score was created (AS: 0-12) as the sum of LIN, MB, HB and PSF, but not FC. A system for severity of NAFLD was developed: Grade 1 (PF: 0-2 and AS: 0-4), Grade 2 (PF: 3 or AS: 5-7) and Grade 3 (PF: 4-6 or AS: 8-12). Diabetes, elevated alkaline phosphatase and decreased platelets were associated with advanced grade. CONCLUSIONS: This simple, reproducible NAFLD score produces a three-tier severity grade. This numerical system may prove useful in assessing disease severity and interval changes.
Adult↗
Sex difference in the development of fatty liver by orotic acid.
Effects of orotic acid on liver lipid accumulation and incorporation of methionine [methyl-14C] into liver phosphatidylcholine and protein, and into serum beta-lipoprotein were studied. Male and female rats of Wistar strain were fed a semisynthetic diet supplemented with 1 per cent orotic acid for 7 days. Feeding of orotic acid induced a marked fatty liver in female rats, but not in males. In female rats, radioactivity in liver phosphatidylcholine was significantly decreased by orotic acid, and that in liver protein was slightly decreased. In male rats, incorporation of methionine [methyl-14C] into liver phosphatidylcholine and protein was unchanged between the control and the rats fed orotic acid. Radioactivity in serum beta-lipoprotein was decreased to a greater extent in female rats than in males. These results suggest that sex difference in the development of fatty liver may be due to the difference in the effect of orotic acid on liver phosphatidylcholine biosynthesis.
Acetates↗
Weight reduction and ursodeoxycholic acid in subjects with nonalcoholic fatty liver disease. A double-blind, placebo-controlled trial.
OBJECTIVE: Nonalcoholic fatty liver disease is an increasingly recognized condition that may progress to end-stage liver disease. We investigated the effects of weight reduction and ursodeoxycholic acid administration in patients with this disease. RESEARCH METHODS AND PROCEDURES: A double-blind, placebo-controlled trial. Twenty-seven women with a body mass index of >30 kg/m2 and willing to participate in the diet plan for six weeks were studied were assigned to one of two treatment groups (ursodeoxycholic acid, n = 14: placebo n = 13). Both groups received a normal diet (1,200 kcal/d) plus 1200 mg/d of ursodeoxycholic acid or placebo. Hepatic steatosis, was assessed by abdominal ultrasound. Fasting glucose, cholesterol, triglycerides, and aminotransferases levels were determined before and after treatment. RESULTS: Body mass index decreases significantly from 34.2 +/- 4.2 kg/m2 and 33.3 +/- 1.6 kg/m2 to 31.8 +/- 4.5 kg/m2 and 30.6 +/- 2.6 kg/m2 in the ursodeoxycholic acid and placebo groups, p < 0.001. The hepatic steatosis index decreased from 2.3 +/- 0.7 to 1.0 +/- 0.6 and 2.2 +/- 0.7 to 1.1 +/- 0.7 in the ursodeoxycholic acid and placebo groups, p<0.003. Serum AST decreased significantly from 41.2 +/- 5.6 to 34.5 +/- 3.4 in the ursodeoxycholic acid group, p <0.001, and from 43.6 +/- 4.2 to 35.3 +/- 2.9 in the placebo group, p <0.001. Serum ALT decreased from 62.9 +/- 6.5 to 44.0 +/- 3.5 in the ursodeoxycholic acid group, p <0.001, and from 63.5 +/- 4.5 to 44.0 +/- 3.5 in the placebo group. We did not find any differences in all variables studied between groups. CONCLUSIONS: The present study shows beneficial effect of weight reduction, producing improvements in biochemical and imaging markers of liver disease.
Adult↗
[Punch biopsy in the diagnosis of fatty liver].
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Biopsy↗
Characterization of crystalline rat liver fatty acid binding protein produced in Escherichia coli.
The principal absorptive cell of the rat small intestinal epithelium contains two homologous cytosolic proteins that bind long chain fatty acids. These are known as intestinal and liver fatty acid binding proteins (FABP). While their precise physiological roles have not been defined, they are believed to represent a multifunctional cytosolic transport system that is involved in the trafficking of exogenous lipids to sites of metabolic processing. 13C NMR studies have revealed differences in their fatty acid binding stoichiometries, binding mechanisms, and the ionization properties of bound fatty acids. To understand the functional differences, liver FABP has been crystallized for eventual comparison with the known crystal structure of intestinal FABP. The lattice type is trigonal with unit cell dimensions of a = b = 84.1 A and c = 44.2 A. The space group as determined by examination of the Patterson symmetry is either P3(1)21 or P3(2)21.
Amino Acid Sequence↗
Effects of pyridoxine deficiency on the composition of plasma and liver fatty acids in rats fed low and high fat diets.
A study was made of the effect of pyridoxine deficiency on the fatty acids of liver and plasma in rats fed diets containing 1, 10, or 20% fat. Both ad libitum-fed and pair-fed control rats were used. In pyridoxine deficiency, arachidonic acid decreased with a concomitant increase in linoleic acid. Incubation of liver slices with [1-14C]acetate showed no significant alteration of fatty acid synthesis in pyridoxine-deficient rats fed 1 or 10% fat when compared with the ad libitum-fed control rats, but revealed a marked increase in cholesterogenesis compared with either control group. Incubations with [1-14C]linoleate resulted in no differences in the synthesis of arachidonate between the experimental and the ad libitum-fed control rats. Incubations with [5,6,8,9,11,12,14,15-3H]arachidonate showed decreased incorporation of this fatty acid in total liver lipids in pyridoxine-deficient rats compared with ad libitum fed control rats. We concluded that the diminution in arachidonate observed in liver lipids of pyridoxine-deficient rats does not result from a lower conversion of linoleate into arachidonate, but possibly from an increased degradation of this fatty acid.
Animals↗
The prevalence of autoantibodies and autoimmune hepatitis in patients with nonalcoholic Fatty liver disease.
OBJECTIVES: Autoantibodies may exist in serum of patients with nonalcoholic fatty liver disease (NAFLD) although their prevalence and clinical significance is uncertain. We aimed at examining the prevalence of autoantibodies and autoimmune hepatitis among patients with NAFLD. METHODS: Prevalence of antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), and autoimmune hepatitis (AIH) based on the International AIH Group were determined in 225 patients with liver biopsy-proven NAFLD. RESULTS: Fifty-one patients [23% (95% CI 17.3-28.2%)] had autoantibodies in serum which is significantly higher than the prevalence in the general population. ANA were present in 46 patients (20%), SMA in 6 (3%), and both antibodies in one patient. Positive autoantibodies were associated with higher fibrosis stage (p= 0.03), higher inflammatory grade (p= 0.02), and higher levels of gammaglobulin (p= 0.01). Prior to liver biopsy, 45 of the 51 (88%) patients with positive autoantibodies fulfilled diagnostic criteria for 'probable' or 'definite' AIH. After liver biopsy, however, only four patients fulfilled diagnostic criteria. CONCLUSIONS: Routinely measured autoantibodies are present in one quarter of patients with NAFLD and are associated with more severe histological damage. Liver biopsy is required to rule out AIH in most NAFLD patients with positive autoantibodies.
Adolescent↗
Detection of haptoglobin in the high-density lipoprotein and the very high-density lipoprotein fractions from sera of calves with experimental pneumonia and cows with naturally occurring fatty liver.
In addition to the lipoprotein-deficient d > 1.25 fraction, haptoglobin was detected in the high-density lipoprotein (HDL) and the very high-density lipoprotein (VHDL) fractions from sera of calves with experimental pneumonia and cows with naturally occurring fatty liver. It was not found in the chylomicrons, very low-density lipoprotein and low-density lipoprotein fractions. Washing of the HDL fraction did not decrease the haptoglobin concentration. Transferrin and immunoglobulin G were immunoblotted to examine the possibility of contamination of the lipoprotein fractions by the d > 1.25 fraction. The two serum proteins were detected only in the d > 1.25 fraction, not in any lipoprotein fractions. The distribution pattern of haptoglobin in the lipoprotein fractions was distinct from that of serum albumin. Concentrations of haptoglobin in the HDL fractions from pneumonic sera were largely proportional to those in whole sera. Cholesteryl ester concentrations were decreased in sera from calves with pneumonia, as in cows with fatty liver. A protein immunologically related to hemoglobin was also detected in particular in the VHDL fractions from sera of both groups. These results suggest that haptoglobin or a complex with the hemoglobin-like protein may have a role or roles related to the lipid metabolism.
Animals↗