Studies on lipogenesis in vivo: Comparison of cholesterol and fatty acid synthesis in rats and mice.
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ABSTRACT:
SUBMITTER: Jansen GR
PROVIDER: S-EPMC1270337 | biostudies-other | 1967 Mar
REPOSITORIES: biostudies-other
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Project description:1. Lipogenesis has been studied in intact genetically obese mice by measuring the incorporation of a single oral dose of 250mg. of [U-(14)C]glucose into fatty acid and cholesterol in the liver and extrahepatic tissues. Studies were also carried out with [U-(14)C]glucose added to the diet and fed for 24hr. With either method of isotope administration, the conversion of [U-(14)C]glucose into fatty acid was greatly elevated in the livers of the obese mice. In contrast, conversion of the single dose of [(14)C]glucose into fatty acid in extrahepatic tissues of obese mice was only half that occurring in the non-obese litter mates. When [(14)C]glucose was given in the diet for 24hr. the total accumulation of labelled fatty acid in extrahepatic tissues of obese mice was slightly less than in the non-obese. Uptake of labelled glucose and conversion into fatty acid in adipose tissue of the obese mice decreased with age. 2. Conversion of the single dose of [(14)C]glucose into liver cholesterol was comparable in obese and non-obese mice fed on a purified low-fat diet. However, obese mice given this diet for 12 weeks accumulated 1.54% of cholesterol in the liver compared with 0.29% in the non-obese litter mates. This accumulation apparently resulted from a decrease in removal of cholesterol from the liver, rather than an increased synthesis. 3. Conversion of the single dose of [(14)C]glucose into extrahepatic fatty acid was decreased by 18hr. starvation proportionally as much in obese as in non-obese mice. The decrease in liver fatty acid synthesis caused by starvation also was considerable in obese mice, although somewhat less marked than in the non-obese. 4. The metabolic derangements in the liver could be more fundamental to the development of the obesity than the changes seen in extrahepatic tissues.
| S-EPMC1270338 | biostudies-other
Project description:1. Lipogenesis in vivo has been studied in mice given a 250mg. meal of [U-(14)C]glucose (2.5muc) or given an intraperitoneal injection of 25mug. of [U-(14)C]glucose (2.0muc). 2. The ability to convert a [U-(14)C]glucose meal into fatty acid was not significantly depressed by 6-7hr. of starvation. In contrast, incorporation of (14)C into fatty acid in the liver after the intraperitoneal dose of [(14)C]glucose was depressed by 80% and by more than 90% by 1 and 2hr. of starvation respectively. Carcass fatty acid synthesis from the [U-(14)C]glucose meal was not depressed by 12hr. of starvation, whereas from the tracer dose of [U-(14)C]glucose the depression in incorporation was 80% after 6hr. of starvation. 3. Re-feeding for 3 days, after 3 days' starvation, raised fatty acid synthesis and cholesterol synthesis in the liver fivefold and tenfold respectively above the levels in non-starved control mice. These increases were associated with an increased amount of both fatty acid and cholesterol in the liver. 4. After 18hr. of starvation incorporation of a [U-(14)C]glucose meal into carcass and liver glycogen were both increased threefold.
| S-EPMC1270189 | biostudies-other
Project description:1. Studies in vivo have been carried out on hepatic and extrahepatic cholesterol synthesis and also on the effects of starvation and re-feeding on both cholesterol and fatty acid synthesis. 2. In rats and mice fed on a stock diet, extrahepatic tissues accounted for about 4 times as much newly synthesized cholesterol as did the liver. The liver appeared to be somewhat more important in the rat than the mouse. Feeding with cholesterol greatly decreased and cholestyramine greatly increased hepatic cholesterol synthesis without much effect on extrahepatic synthesis. 3. Mice starved for up to 7hr. did not lose any of the ability to convert a [U-(14)C]glucose meal into fat, whereas 18hr. of starvation resulted in an 80% loss of fatty acid synthesis in liver and carcass, an 80% loss in liver cholesterol synthesis and a 65% decrease in carcass cholesterol synthesis; 18hr. of food deprivation also decreased the proportion of counts in epididymal fat pads present as fat and increased the proportion present as glyceride glycerol. 4. Re-feeding for up to 7hr. restored fatty acid synthesis from a [U-(14)C]glucose meal to about 50% of the values for non-starved mice but had no effect on hepatic cholesterol synthesis. The altered distribution of counts in the epididymal fat pads caused by starvation was restored to normal after feeding for 1hr.
| S-EPMC1265001 | biostudies-other
Project description:1. An inverse logarithmic relationship was found between lipogenesis and the concentration of serum free fatty acids perfusing the rat liver. 2. Increased concentrations of serum free fatty acids did not alter cholesterol synthesis, triglyceride secretion or increase gluconeogenesis. 3. No direct relationship was found between ketogenesis and either lipogenesis or gluconeogenesis.
| S-EPMC1167977 | biostudies-other
Project description:In the present study, the beneficial effects of proteasome inhibitor treatment in reducing ethanol-induced steatosis were investigated. A microarray analysis was performed on the liver of rats injected with PS-341 (Bortezomib, Velcade), and the results showed that proteasome inhibitor treatment significantly reduced the mRNA expression of SREBP-1c, and the downstream lipogenic enzymes, such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. ELOVL6, which is responsible for fatty acids long chain elongation, was also significantly downregulated by proteasome inhibitor treatment. Moreover, PS-341 administration significantly reduced the expression of acyl-glycerol-3-phosphate acyltransferase (AGPAT), and diacylglycerol acyltransferase (DGAT), enzyme involved in triacylglycerol (TAG) synthesis. Finally, PS-341 was found to downregulate the enzyme 3-hydroxy-3-methylglutaryl-CoenzymeA synthase (HMG-CoA synthase) that is responsible for cholesterol synthesis. Proteasome inhibitor was also found to play a role in intestinal lipid adsorption because apolipoproteins A (apoA-I, apoAII, apoA-IV and ApoCIII) were downregulated by proteasome inhibitor treatment, especially ApoA-II that is known to be a marker of alcohol consumption. Proteasome inhibitor treatment also decreased apobec-1 complementation factor (ACF) leading to lower level of editing and production of ApoB protein. Moreover apolipoprotein C-III, a major component of chylomicrons was significantly downregulated. However, lipoprotein lipase (Lpl) and High density lipoprotein binding protein (Hdlbp) mRNA levels were increased by proteasome inhibitor treatment. These results suggested that proteasome inhibitor treatment could be used to reduce the alcohol-enhanced lipogenesis and alcohol-induced liver steatosis. A morphologic analysis, performed on the liver of rats fed ethanol for one month and treated with PS-341, showed that proteasome inhibitor treatment significantly decreased ethanol-induced liver steatosis. SREBP-1c, FAS and ACC were increased by ethanol feeding alone, but were significantly decreased when proteasome inhibitor was administered to rats fed ethanol. Our results also show that both mRNA and protein levels of these lipogenic enzymes, up regulated by ethanol, were then downregulated when proteasome inhibitor was administered to rats fed ethanol. It was also confirmed that alcohol feeding caused an increase in AGPAT and DGAT, which was prevented by proteasome inhibitor treatment of the animal fed ethanol. Chronic alcohol feeding did not affect the gene expression of HMG-CoA synthase. However, PS341 administration significantly reduced the HMG-CoA synthase mRNA levels, confirming the results obtained with the microarray analysis. C/EBP transcription factors alpha (CCAAT/enhancer-binding protein alpha) has been shown to positively regulate SREBP-1c mRNA expression, thus regulating lipogenesis. Proteasome inhibition caused a decrease in C/EBP alpha mRNA expression, indicating that C/EBP downregulation may be the mechanism by which proteasome inhibitor treatment reduced lipogenesis. In conclusion, our results indicate that proteasome activity is not only involved in downregulating fatty acid synthesis and triacylglycerol synthesis, but also cholesterol synthesis and intestinal lipid adsorption. Proteasome inhibitor, administrated at a non-toxic low dose, played a beneficial role in reducing lipogenesis caused by chronic ethanol feeding and these beneficial effects are obtained because of the specificity and reversibility of the proteasome inhibitor used.
| S-EPMC4197193 | biostudies-literature
Project description:Previous studies suggested that high consumption of saturated fatty acid (SFA) is a risk factor for liver cancer. However, it remains unclear how dietary SFA affects liver tumorigenesis. This study aimed to investigate the impact of a SFA-rich diet on hepatic tumorigenesis using hepatitis C virus core gene transgenic (HCVcpTg) mice that spontaneously developed hepatic steatosis and tumors with aging. Male HCVcpTg mice were treated for 15 months with a purified control diet or SFA-rich diet prepared by replacing soybean oil in the control diet with hydrogenated coconut oil, and phenotypic changes were assessed. In this special diet, almost all dietary fatty acids were SFA. Long-term feeding of SFA-rich diet to HCVcpTg mice increased hepatic steatosis, liver dysfunction, and the prevalence of liver tumors, likely due to stimulation of de novo lipogenesis, activation of the pro-inflammatory and pro-oncogenic transcription factor nuclear factor-kappa B (NF-κB), enhanced c-Jun N-terminal kinase/activator protein 1 (JNK/AP-1) signaling and induction of the oncogenes cyclin D1 and p62/sequestosome 1. The SFA-rich diet did not affect liver fibrosis or autophagy. Collectively, long-term SFA-rich diet consumption promoted hepatic tumorigenesis mainly through activation of lipogenesis, NF-κB, and JNK/AP-1 signaling. We therefore propose that HCV-infected patients should avoid excessive intake of SFA-rich foods to prevent liver cancer.
| S-EPMC7756930 | biostudies-literature
Project description:Nonalcoholic steatohepatitis (NASH) is a rapidly growing cause of chronic liver damage, cirrhosis, and hepatocellular carcinoma. How fatty liver pathogenesis is subject to epigenetic regulation is unknown. We hypothesized that chromatin remodeling is important for the pathogenesis of fatty liver disease. AT-rich interactive domain-containing protein 1A (ARID1A), a DNA-binding component of the SWItch/sucrose nonfermentable adenosine triphosphate-dependent chromatin-remodeling complex, contributes to nucleosome repositioning and access by transcriptional regulators. Liver-specific deletion of Arid1a (Arid1a liver knockout [LKO]) caused the development of age-dependent fatty liver disease in mice. Transcriptome analysis revealed up-regulation of lipogenesis and down-regulation of fatty acid oxidation genes. As evidence of direct regulation, ARID1A demonstrated direct binding to the promoters of many of these differentially regulated genes. Additionally, Arid1a LKO mice were more susceptible to high-fat diet-induced liver steatosis and fibrosis. We deleted Pten in combination with Arid1a to synergistically drive fatty liver progression. Inhibition of lipogenesis using CAT-2003, a potent sterol regulatory element-binding protein inhibitor, mediated improvements in markers of fatty liver disease progression in this Arid1a/Pten double knockout model. Conclusion: ARID1A plays a role in the epigenetic regulation of hepatic lipid homeostasis, and its suppression contributes to fatty liver pathogenesis. Combined Arid1a and Pten deletion shows accelerated fatty liver disease progression and is a useful mouse model for studying therapeutic strategies for NASH.
| S-EPMC6461494 | biostudies-literature
Project description:Metabolic diseases are closely linked to aberrant synthesis of endogenous fatty acids in the liver, called de novo lipogenesis (DNL), which is mediated by the enzyme fatty acid synthase (FASN). The composition of complex lipids consists of saturated or monosaturated fatty acids, which can be endogenously produced, and polyunsaturated fatty acids (PUFA), which are strictly dietary. Compositional differences between individuals are insufficiently understood and may influence the onset and progression of metabolic and cardiovascular diseases. Here we show that DNL critically determines the use of dietary PUFA. A patient with a hypofunctional heterozygous de novo Arg2177Cys variant in FASN exhibited an elevated composition of PUFA, which was phenocopied by pharmacological inhibition of FASN with TVB-2640 in patients with nonalcoholic steatohepatitis (NASH). In mice, the incorporation rate of supplemented omega-3 PUFA during an obesogenic diet was increased by genetic or pharmacologic reduction of DNL. Mechanistically, we show that the FASN variant exhibited a cysteine-dependent, non-enzymatic acetylation of FASN, which resulted in hyperubiquitinylation and decreased protein stability. Our study further reveals that PUFA storage is an active, enzymatic process controlled by FASN, diacylglycerol O-acyltransferase 2 (DGAT2) and MFSD2A, a membrane-transport protein, and that combining FASN inhibition and PUFA supplementation exerts additive beneficial metabolic effects. These findings provide evidence that the success of PUFA supplementation may depend on the rate of endogenous DNL and that combined PUFA supplementation and FASN inhibition may be a promising approach targeting metabolic disease.
2023-12-19 | PXD045908 | Pride
Project description:Non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), hepatic fibrosis and even hepatocellular carcinoma, is a liver disease worldwide without approved therapeutic drugs. Baicalein (BAL), a flavonoid compound extracted from the Traditional Chinese Medicine (TCM) Scutellariae Radix (Scutellaria baicalensis Georgi.), has been used in TCM clinical practice for thousands of years to treat liver diseases due to its "hepatoprotective effect". However, the underlying liver-protecting mechanisms remain largely unknown. Here, we found that oral administration of BAL significantly decreased excess serum levels of triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST) as well as hepatic TG in fructose-fed rats. Attenuation of the increased vacuolization and Oil Red O staining area was evident on hepatic histological examination in BAL-treated rats. Mechanistically, results of RNA-sequencing, western-blot, real-time quantitative PCR (RT-qPCR) and hepatic metabolomics analyses indicated that BAL decreased fructose-induced excessive nuclear expressions of mature sterol regulatory element-binding protein 1c (mSREBP1c) and carbohydrate response element-binding protein (ChREBP), which led to the decline of lipogenic molecules [including fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), elongation of very long chain fatty acids 6 (ELOVL6), acetyl-CoA carboxylase (ACC)], accompanying with the alternation of hepatic fatty acids composition. Meanwhile, BAL enhanced fatty acid oxidation by activating AMPK/PGC1α signaling axis and PPARα signal pathway, which elicited high expression of carnitine palmitoyl transferase 1α (CPT1α) and Acyl-CoA oxidase 1 (ACO1) in livers of fructose-fed rats, respectively. BAL ameliorated fructose-induced hepatic steatosis, which is associated with regulating fatty acid synthesis, elongation and oxidation.
| S-EPMC9280198 | biostudies-literature
Project description:Hepatic steatosis is associated with detrimental metabolic phenotypes including enhanced risk for diabetes. Stearoyl-CoA desaturases (SCDs) catalyze the synthesis of MUFAs. In mice, genetic ablation of SCDs reduces hepatic de novo lipogenesis (DNL) and protects against diet-induced hepatic steatosis and adiposity. To understand the mechanism by which hepatic MUFA production influences adipose tissue stores, we created two liver-specific transgenic mouse models in the SCD1 knockout that express either human SCD5 or mouse SCD3, that synthesize oleate and palmitoleate, respectively. We demonstrate that hepatic de novo synthesized oleate, but not palmitoleate, stimulate hepatic lipid accumulation and adiposity, reversing the protective effect of the global SCD1 knockout under lipogenic conditions. Unexpectedly, the accumulation of hepatic lipid occurred without induction of the hepatic DNL program. Changes in hepatic lipid composition were reflected in plasma and in adipose tissue. Importantly, endogenously synthesized hepatic oleate was associated with suppressed DNL and fatty acid oxidation in white adipose tissue. Regression analysis revealed a strong correlation between adipose tissue lipid fuel utilization and hepatic and adipose tissue lipid storage. These data suggest an extrahepatic mechanism where endogenous hepatic oleate regulates lipid homeostasis in adipose tissues.
| S-EPMC4306685 | biostudies-literature