Histological and biochemical indices of progressive liver injury in patients with alcoholic fatty liver.
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Animals↗
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Accentuation of white phosphorus induced fatty liver by phenobarbitone in male rats compared to female rats.
The possible influence of a potent enzyme inducer, phenobarbitone, on white phosphorus fatty liver, was studied. Pretreatment by phenobarbitone for four days in white phosphorus poisoned rats provoked a decrease in mortality and an increase in hepatic triglycerides (fatty liver) in male rats. The activity of uridine diphosphoglucuronyl transferase (UDPGT), an inducible enzyme, is not modified by this pretreatment in white phosphorus poisoned rats. The accentuation of white phosphorus fatty liver by phenobarbitone in male rats could be explained by an increased hydroxylation of testosterone, thus counteracting the protective effect of this hormone on fatty liver.
Animals↗
Factors affecting the reassociation and reactivation of the half-molecular weight nonidentical subunits of pigeon liver fatty acid synthetase.
The pigeon liver fatty acid synthetase complex (14 S) is dissociated in low ionic strength buffer containing dithiothreitol to form a half-molecular weight subunits (9 S) which are completely inactive for the synthesis of saturated fatty acids. The dithiothreitol-protected (reduced) subunits are rapidly reassociated and reactivated to form the active enzyme complex, not only by an increase in salt concentration but also by micromolar concentrations of NADP+ or NADPH. Increases in KCl or NADPH concentration result in an increase in the extent of reactivation (equilibrium) with no change in the over-all rate of the reaction or the half-life ofreactivation of the enzyme. The extent (equilibrium) of reactivation of the enzyme is the same in 0.2 M potassium phosphate buffer, pH 7.0; 0.2 M KCl in 5 mM Tris-35 mM glycine buffer, PH 8.3; and 50 muM NADP+ or NADPH in the Tris-glycine buffer. The extent and rate of reactivation of the enzyme is dependent not only on ionic strength and NADPH concentration, but also on pH and temperature. Reactivation with 0.2 M KCl is optimal between pH 7.3 and 8.5. At higher and lower pH values the rate and extent of reactivation are lowered. The rate and extent of reactivation are also decreased as the temperature is lowered below 10 degrees. At 0 degrees there is little reactivation of enzyme activity. However, in the presence of 0.2 M KCl containing 15 to 40% glycerol at 0 degrees, reactivation of the enzyme is about 50% complete. The rate of reactivation of enzyme in the presence of KCl or NADPH conforms to first order kinetics. This result suggests that the subunits first combine to form an inactive complex which is subsequently transformed to an enzymatically active complex. Evidence for the presence of inactive complex was obtained in experiments carried out in 0.2 M KCl at pH 6.0, and in 0.2 M KCl at pH 8.3, at both 6 and 3 degrees. Under these conditions the amount of complex observed upon ultracentrifugation was greater than expected from determinations of enzyme activity. The above findings suggest that ionic and hydrophobic interactions, and possibly the water structure surrounding the interacting sites, are of prime importance in reassociation and reactivation of enzyme. In addition, NADP+ and NADPH have very specific effects in bringing about reassociation and in maintaining the structural integrity of the multienzyme complex.
Animals↗
Serum and body characteristics of laying hens with fatty liver syndrome.
Commercial laying hens with Fatty Liver Syndrome had greatly elevated levels of serum calcium and cholesterol. Most of the hens with the elevated serum calcium and cholesterol were out of production, but some were still in production. Hens with elevated calcium and cholesterol levels had extremely large combs and excessive deposits of fat in the abdomen.
Adipose Tissue↗
Translation of rat liver fatty acid synthetase mRNA in a cell-free system derived from wheat germ.
Total liver polysomes were isolated from rats that had fasted for 48 hr and that then had been re-fed a high-carbohydrate, fat-free diet for 20-24 hr. Indirect immunoprecipitation of the polysomes with purified antibody to rat liver fatty acid synthetase and deproteination on sodium dodecyl sulfate-containing sucrose gradients gave an RNA fraction which, when translated in a cell-free system derived from wheat germ, yielded a major polypeptide of apparent molecular weight 225,000 when the translation products were analyzed by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. The polypeptide was specifically precipitated with antibody against rat liver fatty acid synthetase and competed with unlabeled fatty acid synthetase for binding to the antibody. It was somewhat smaller than native fatty acid synthetase subunits (molecular weight 240,000). The peptide accounted for approximately 65% of the radioactive, antibody-precipitable product, the remainder being peptides in the molecular weight range 100,000-150,000. Synthesis of the polypeptide was optimized with respect to K(+), Mg(2+), and spermine concentrations. The quantity of fatty acid synthetase mRNA obtained by the above procedure and measured by translation was a function of the nutritional state of the animal. The relative activity in fasting rats compared to rats that were re-fed for 12 hr was 1:12. The data suggest that rat liver fatty acid synthetase is synthesized as intact subunits from a large mRNA molecule or molecules.
Animals↗
Newly identified single-nucleotide polymorphism associated with the transition from nonalcoholic fatty liver disease to liver fibrosis: results from a nested case-control study in the UK biobank.
BACKGROUND: Genetic factors may have a significant influence on the likelihood of liver fibrosis in individuals with nonalcoholic fatty liver disease (NAFLD). The present study was conducted to explore how single-nucleotide polymorphism (SNP) impacts the development of fibrosis in those suffering from NAFLD. MATERIALS AND METHODS: Utilizing the UK Biobank dataset, we conducted a nested case-control analysis among NAFLD participants, defining the case group as those with liver fibrosis and cirrhosis during follow-up. For our in vitro investigations, we employed the LX-2 human hepatic stellate cell line. Our procedures included cultivating these cells, employing SAMM50-rs2073080 plasmid techniques to enhance the expression of recently discovered SNPs, and conducting biochemical assays. To quantify gene expression, we used real-time PCR with fluorescence detection. RESULTS: The study analyzed data from 5467 participants (1094 cases and 4373 controls). Genome-wide association analysis identified nine significant loci, including the novel rs2073080 variant, strongly associated with NAFLD-associated hepatic fibrosis. In vitro TGF-β modeling revealed significant upregulation of α-SMA and COL1A1, confirming model effectiveness. Oxidative stress markers like elevated malondialdehyde (MDA) and reduced catalase (CAT) and superoxide dismutase (SOD) levels indicated liver damage in the TGF-β group. SAMM50-rs2073080 was upregulated in the NAFLD-associated fibrosis model. In vitro experiments on LX-2 cells showed that SAMM50-rs2073080 overexpression led to increased fibrosis, as indicated by higher cellular MDA levels and lower CAT and SOD levels, compared to the vector group. CONCLUSION: Our research highlights a significant association of SAMM50-rs2073080 with the progression of NAFLD to hepatic fibrosis, and the in vitro experiments further corroborated these findings.
Humans↗
Mechanism for fatty liver induction in rats fed arginine deficient diets.
Arginine deficiency is known to lead to marked alterations in pyrimidine biosynthesis and the excessive loss of urinary orotic acid. Orotic acid feeding is known to lead to hepatic steatosis. These studies show that arginine deficiency also results in a marked increase in liver lipids in the rat. The majority of the increased liver lipid can be accounted for by triglyceride accumulation. Increased liver lipid infiltration was found to be independent of the sex of the rat. Accompanying this increase was a decrease in serum triglycerides and cholesterol concentrations. Fatty infiltrations induced by arginine deficiency could be reversed by refeeding an arginine enriched diet. Adenine supplementation (0.30%) to the arginine deficient diet also completely prevented the induction of fatty livers. Adenine supplementation resulted in a dramatic increase in urinary orotic acid excretion in the arginine deficient rat. Guanine supplementation (0.5%) to an arginine deficient diet reduced but did not prevent the induction of fatty livers. The similarities of fatty livers induced by arginine deficiency and orotic acid feeding are discussed.
Adenine↗
[Treatment of alcoholic toxic fatty liver. A placebo-controlled trial with hepavis (author's transl)].
A placebo-controlled double-blind study of 30 patients with advanced chronic fatty liver was intended to show how far treatment with a liver preparation, in this case Hepavis, is superior to alcohol abstinence alone. Examination of the laboratory parameters, especially of gamma GT shows that treatment with Hepavis with simultaneous withdrawal of alcohol produces a rapid normalization or improvement of the laboratory findings and consequently an accelerated improvement in the course of the disease. This leads to the conclusion that the pathological activity of the liver cell is reduced more quickly by the constituents of Hepavis than without suitable therapy, and that a more favorable prognosis for the fatty liver as a potential precurser of cirrhosis is to be attained. Not only is elimination of the lipogenic factor, alcohol, essential in the treatment of fatty liver, but also treatment with hepatotropic substances.
Adult↗
Changes in plasma lipid and glucose levels during the onset of fatty liver and kidney syndrome in chics.
Plasma glucose, free fatty acid and triglyceride levels were measured during the onset of fatty liver and kidney syndrome in chicks. Intial studies indicated that behavioural and clinical changes characteristically associated with the syndrome were observed only during the 24 h preceding death. A more detailed examination of the blood changes was made on fasted birds. Typically, affected birds could be distinguished from healthy fasted birds by a hypoglycaemia which developed within 2.5 h of the removal of food, and a slightly higher and more sustained elevation of free fatty acid levels. Triglyceride values were not generally different from those found in normal birds. Although moderate to large amounts of lipid were occasionally observed in the kidneys of healthy fasted birds, only in affected birds was significant lipid infiltration of the kidneys associated with a similar level of lipid infiltration of the liver. In extreme cases death from fatty liver and kidney syndrome could occur within 4 h of the removal of food.
Animals↗
Metabolic studies on the development of ethanol-induced fatty liver in KK-Ay mice.
Mechanisms involved in the development of the alcoholic fatty liver in KK-Ay mice were investigated. Incorporation studies using [14C]acetate and [3H]palmitate indicated that the half-life of hepatic triglycerides was doubled in the ethanol-ingesting mice, and utilization of the exogenous fat was significantly increases as compared with that of the control. No persistent alteration was recognized in hepatic oxidation of palmitate, as estimated by in vitro experiments using liver slices obtained from control and ethanol-drinking mice. Enzymic studies indicated that the activities of acetyl COA carboxylase, ATP citrate lyase, malic enzyme, and 6-phosphogluconate dehydrogenase were increased with ethanol drinking. The increment in hepatic triglycerides accumulated during ethanol ingestion was largely accounted for by palmitoleic, oleic, and linoleic acids. These findings demonstrated an augmentation in hepatic lipogenesis as well as an increased utilization of exogenous fats. Ethanol drinking did not cause any appreciable change in plasma triglyceride level and metabolism of adipose tissue. In summary of the present studies, accelerated lipogenesis and increased utilization of the dietary fats may be possible causal factors in the alcoholic fatty liver of KK-Ay mice.
ATP Citrate (pro-S)-Lyase↗
A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes.
BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined genome-wide association studies of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD. APPROACH AND RESULTS: We used the UK Biobank to explore the associations of our novel MASLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study MASLD genes in vitro using CRISPRi. Our data identify VKORC1 , TNKS , LYPLAL1 , and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of MASLD. CONCLUSIONS: Complementary genetic and genomic approaches are useful for the identification of MASLD genes. Our data supports VKORC1 as a bona fide MASLD gene. We have established a functional genomic framework to study at scale putative novel MASLD genes from human genetic association studies.
Humans↗
Fatty liver in hypervitaminosis A: synthesis and release of hepatic triglycerides.
Feeding large doses (30,000 IU/100 g body wt per day) of vitamin A to young rats for 2 days produced fatty liver, caused a stimulation of oxidation and esterification of [1-14C]palmitate by liver slices, and increased the activity of hepatic palmitoyl-CoA synthetase. Under similar conditions, however, release of hepatic triglycerides into the plasma, as judged from the post-Triton triglyceridemia, remained unaffected. It is indicated by the present findings that excessive intake of vitamin A produces fatty liver by stimulating the synthesis of triglycerides in liver without affecting the rate of secretion of hepatic triglycerides. An involvement of altered oxidation of fatty acids in the liver can also be ruled out because in hypervitaminosis A this process is increased rather than decreased as required for fatty liver production.
Acetoacetates↗
Nonalcoholic fatty liver with alcoholic hyalin after long-term glucocorticoid therapy.
Alcoholic hyalin was found in liver of a nonalcoholic patient with fatty liver after long-term glucocorticoid therapy for systemic lupus erythematosus. Hepatocytes including hyalin bodies showed fatty change or vesiculated degeneration. Occasionally, basophilic substance which was recognized in the hepatocytes with or without hyalin was noticed showing the feature quite similar to delicate alcoholic hyalin.
Adult↗
Early perivenular sclerosis in alcoholic fatty liver: an index of progressive liver injury.
Alcoholic steatosis was associated with sclerosis around the terminal hepatic venules in liver biopsies of 40% of chronic alcoholics but not in those of moderate drinkers. To determine whether this sclerosis could be a precursor lesion of cirrhosis, controlled studies were performed in animal models. In the alcohol-fed baboons that developed fibrosis or cirrhosis, progressive perivenular sclerosis invariably started at the fatty liver stage before or even more commonly in the absence of alcoholic hepatitis. No sclerosis occurred in controls or in alcohol-fed baboons and rats that did not progress beyond the fatty liver stage. The clinical and experimental data indicate that sclerosis around the terminal venules, a common but often overlooked complication of alcoholic fatty liver, reflects heavy prolonged drinking, and may identify those patients who are susceptible to develop the more advanced lesions of alcoholic liver injury upon continued drinking.
Adult↗
The biochemistry of fatty liver and kidney syndrome. Biotin-mediated restoration of hepatic gluconeogenesis in vitro and its relationship to pyruvate carboxylase activity.
Liver slices from chicks affected by the fatty liver and kidney syndrome display an extremely low extent of hepatic gluconeogenesis which is associated with decreased activities of certain rate-limiting gluconeogenic enzymes. Pyruvate carboxylase activity is particularly severely affected, being less than 4% of control values. Incubation of affected slices in a biotin-containing nutrient medium restores both gluconeogenesis and pyruvate carboxylase actiivity (the latter to approx. 35% of the control valve). Activities of the other enzymes studied were not greatly affected by this treatment. Restoration of gluconeogenesis did not occur if biotin was excluded from the nutrient medium, nor was it prevented by protein-synthesis inhibitors. It is concluded that the syndrome involves the lack of available biotin in the liver rather than suppression of apocarboxylase synthesis.
Animals↗
[Studies on the fatty liver problem in the laying hen. IV. Effect of isocaloric fatty diets on liver fat metabolism in hens kept in cages].
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Animals↗
Human Umbilical Cord Mesenchymal Stem Cells in Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD) Therapy: Mechanisms, Clinical Efficacy, and Future Perspectives.
There is currently no approved drug treatment for metabolic dysfunction-related fatty liver disease (MAFLD). Umbilical cord-derived mesenchymal stem cells (UC-MSCs) show therapeutic potential, but their mechanism of action is remains incompletely understood. Different from previous reviews that focused on a single pathway, this article presents three important contributions: First, it constructs an integrated "multi-target synergy network" model, clarifying how UC-MSCs coordinate and regulate the inflammatory, metabolic and fibrotic processes through the interactions between the AMPK/mTOR, Nrf2/HO-1 and TGF-β/Smad pathways; Second, it systematically assesses recent clinical trials (2022-2025), identifying several unaddressed barriers to transformation, including the lack of histological endpoint indicators, batch-to-batch differences, and the absence of dose exploration studies; Third, we integrate the latest developments from 2024 to 2025, particularly mitochondrial transfer (mediated by tunnel nanotubes and accompanied by quantitative efficacy data) and exosome circular RNA networks [Formula: see text], which have not been covered in previous reviews. Based on the above analysis, we also propose specific suggestions for standardized GMP production, mandatory genomic stability testing, and long-term safety registration. This review provides a comprehensive analysis of elaborates on the treatment of MAFLD with UC-MSCs from a mechanistic and translational perspective, based on the extensive updates of relevant literature.
Humans↗
Reduced nicotinamide adenine dinucleotide phosphate, a structural and conformational probe of chicken liver fatty acid synthetase.
Structural and conformational organization of chicken liver fatty acid synthetase has been probed using its fluorescent coenzyme, NADPH. Three NADPH binding sites per mole of the enzyme complex, of apparently identical dissociation constant (KD = 0.6 muM) can be titrated at temperatures above 12 degrees. These results are in disagreement with the earlier studies of Hsu and Wagner (Hsu, R. Y., and Wagner, B. J. (1970) Biochemistry, 9, 245-251) in which four such sites could be titrated. At 12 degrees, the composite sites split into two subsets: a pair of sites with a KD of 0.3 muM and a third site with a Kd of 1.1 muM. At lower temperatures (5 degrees or 2 degrees), the site with weak affinity disappears, leaving a pair of sites with a Kd of 0.5 muM. Similar observations were made when the enzyme was modified with phenylmethylsulfonyl fluoride, a specific and selective inhibitor of fatty acyl-CoA deacylase (s) of the pigeon liver enzyme complex (Kumar, S. (1975) J. Biol. Chem. 250, 5150-5158). Partial modification with phenylmethylsulfonyl fluoride elicits a NADPH binding response similar to the binding observed at 12 degrees, i.e. two sets of binding sites with nonidentical dissociation constants. Further modification corresponding to the complete loss of deacylase function results in a set of two apparently identical binding sites, and the third site is not available for titration. The modified enzyme retains the two reductase functions as measured by the model substrates, acetoacetyl-N-acetylcysteamine and crotonyl-CoA. Furthermore, the addition of acetyl- and malonyl-CoA (100 muM each) to the modified enzyme lowers the NADPH binding affinity by a factor of 3. Other observations show that the quantum yield, as measured by the ratio of fluorescence intensity of bound and free NADPH, changes with temperature and ionic strength. Lowering the temperature from 30 degrees to 2 degrees increases the enhancement ratio by 50%, whereas increase in ionic strength from 0.05 to 0.2 M potassium phosphate lowers it to 50% of the original level. Measurement of NADPH binding in the presence of NADP+, NADH, NAD+ and adenosine-2'-monophospho-5'-diphosphoribose demonstrates that NADP+ shows competitive behavior for NADPH sites (KD = 10.6 muM), whereas NADH and NAD+ show noncompetitive (KD (apparent) = nearly 600 muM) and rather complicated interactions implicating nonspecific conformational alteration of the enzyme complex. The behavior of adenosine 2'-monophospho-5'-diphosphoribose is intermediate between NADP+ and NADH. These data are discussed in terms of substrate-mediated conformational changes and the moles of each of the reductase enzymes per mole of the enzyme complex, the polarity of the NADPH binding region, and the probable structure of the nicotinamide moiety when bound to the enzyme.
Animals↗