Regulation of hepatic lipogenesis by plasma free fatty acids: simultaneous studies on lipoprotein secretion, cholesterol synthesis, ketogenesis and gluconeogenesis.
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ABSTRACT:
SUBMITTER: Mayes PA
PROVIDER: S-EPMC1167977 | biostudies-other | 1974 Apr
REPOSITORIES: biostudies-other
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Project description:Cardiovascular diseases (CVDs) are the most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) and dyslipidemia is considered at least partially responsible for the increased CVD risk in NAFLD patients. The aim of the present study is to understand how hepatic de novo lipogenesis influences hepatic cholesterol content as well as its effects on the plasma lipid levels. Hepatic lipogenesis was induced in mice by feeding a fat-free/high-sucrose (FF/HS) diet and the metabolic pathways associated with cholesterol were then analyzed. Both liver triglyceride and cholesterol contents were significantly increased in mice fed an FF/HS diet. Activation of fatty acid synthesis driven by the activation of sterol regulatory element binding protein (SREBP)-1c resulted in the increased liver triglycerides. The augmented cholesterol content in the liver could not be explained by an increased cholesterol synthesis, which was decreased by the FF/HS diet. HMGCoA reductase protein level was decreased in mice fed an FF/HS diet. We found that the liver retained more cholesterol through a reduced excretion of bile acids, a reduced fecal cholesterol excretion, and an increased cholesterol uptake from plasma lipoproteins. Very low-density lipoproteintriglyceride and -cholesterol secretion were increased in mice fed an FF/HS diet, which led to hypertriglyceridemia and hypercholesterolemia in Ldlr-/- mice, a model that exhibits a more human like lipoprotein profile. These findings suggest that dietary cholesterol intake and cholesterol synthesis rates cannot only explain the hypercholesterolemia associated with NAFLD, and that the control of fatty acid synthesis should be considered for the management of dyslipidemia.
| S-EPMC7941001 | biostudies-literature
Project description:Preservation of bioenergetic homeostasis during the transition from the carbohydrate-laden fetal diet to the high fat, low carbohydrate neonatal diet requires inductions of hepatic fatty acid oxidation, gluconeogenesis, and ketogenesis. Mice with loss-of-function mutation in the extrahepatic mitochondrial enzyme CoA transferase (succinyl-CoA:3-oxoacid CoA transferase, SCOT, encoded by nuclear Oxct1) cannot terminally oxidize ketone bodies and develop lethal hyperketonemic hypoglycemia within 48 h of birth. Here we use this model to demonstrate that loss of ketone body oxidation, an exclusively extrahepatic process, disrupts hepatic intermediary metabolic homeostasis after high fat mother's milk is ingested. Livers of SCOT-knock-out (SCOT-KO) neonates induce the expression of the genes encoding peroxisome proliferator-activated receptor ? co-activator-1a (PGC-1?), phosphoenolpyruvate carboxykinase (PEPCK), pyruvate carboxylase, and glucose-6-phosphatase, and the neonate's pools of gluconeogenic alanine and lactate are each diminished by 50%. NMR-based quantitative fate mapping of (13)C-labeled substrates revealed that livers of SCOT-KO newborn mice synthesize glucose from exogenously administered pyruvate. However, the contribution of exogenous pyruvate to the tricarboxylic acid cycle as acetyl-CoA is increased in SCOT-KO livers and is associated with diminished terminal oxidation of fatty acids. After mother's milk provokes hyperketonemia, livers of SCOT-KO mice diminish de novo hepatic ?-hydroxybutyrate synthesis by 90%. Disruption of ?-hydroxybutyrate production increases hepatic NAD(+)/NADH ratios 3-fold, oxidizing redox potential in liver but not skeletal muscle. Together, these results indicate that peripheral ketone body oxidation prevents hypoglycemia and supports hepatic metabolic homeostasis, which is critical for the maintenance of glycemia during the adaptation to birth.
| S-EPMC3707678 | biostudies-literature
Project description:Short-term exposure of isolated rat hepatocytes to short- and medium-chain fatty acids led to an activation of acetyl-CoA carboxylase as measured in digitonin-permeabilized hepatocytes. Up to a certain concentration, typical for each of the fatty acids used, fatty acid-dependent activation of acetyl-CoA carboxylase coincided with an increase in the rate of fatty acid synthesis in intact hepatocytes, as determined by the incorporation of 3H from 3H2O water into fatty acids. At higher concentrations loss of stimulation of fatty acid synthesis occurred, but not the enhancement of carboxylase activity. With the fatty acids tested (C8:0-C14:0), the peak in fatty acid synthesis coincided with a peak in the level of malonyl-CoA. The onset of the stimulation of carboxylase activity coincided with the start of the peak in both fatty acid synthesis and malonyl-CoA. The longer the chain length of the fatty acid added, the lower the concentration at which the rate of fatty acid synthesis and the level of malonyl-CoA reached a peak and carboxylase activity started to become elevated. In cell suspensions incubated with increasing concentrations of fatty acids, accumulation of lactate decreased progressively. The latter observation, in combination with the fact that the activity of acetyl-CoA carboxylase is not always related to the rate of fatty acid biosynthesis, suggests that under these conditions not the activity of the carboxylase but the flux through the glycolytic sequence determines, at least in part, the rate of fatty acid synthesis de novo.
| S-EPMC1137201 | biostudies-other
Project description:OBJECTIVE:To determine whether n-3 fatty acids (n-3) influence arterial cholesterol delivery and lipoprotein lipase (LpL) levels in insulin-resistant mice. METHODS AND RESULTS:Insulin resistance contributes to risk of cardiovascular disease. It was previously reported that saturated fat (SAT) diets increased, but n-3 diets decreased, arterial low-density lipoprotein (LDL) cholesterol deposition from LDL total and selective uptake; this was associated with increased or decreased arterial LpL, respectively. Insulin receptor transgenic knockout mice (L1) were fed a chow, SAT, or n-3 diet for 12 weeks. Double-fluorescent boron dipyrromethene (BODIPY)-cholesteryl ester (CE) and Alexa dye-labeled human LDL were injected to separately trace LDL-CE and LDL-apolipoprotein B whole particle uptake. In contrast to SAT, n-3 diets markedly reduced all plasma lipids, ameliorating progression of insulin resistance. As opposed to SAT, n-3 reduced arterial LDL uptake, CE deposition, and selective uptake. Disparate patterns of CE deposition between diets were comparable with arterial LpL distribution; SAT induced high LpL levels throughout aortic media; LpL was limited only to intima in n-3-fed mice. CONCLUSIONS:n-3 diets diminish arterial LDL-cholesterol deposition in mice with insulin resistance, and this is associated with changes in arterial LpL levels and distribution.
| S-EPMC3107680 | biostudies-literature
Project description:Long non-coding RNAs (lncRNAs) are emerging important epigenetic regulators in metabolic processes. Whether they contribute to the metabolic effects of vertical sleeve gastrectomy (VSG), one of the most effective treatments for sustainable weight loss and metabolic improvement, is unknown. Herein, we identify a hepatic lncRNA Gm19619, which is strongly repressed by VSG but highly up-regulated by diet-induced obesity and overnight-fasting in mice. Forced transcription of Gm19619 in the mouse liver significantly promotes hepatic gluconeogenesis with the elevated expression of G6pc and Pck1. In contrast, AAV-CasRx mediated knockdown of Gm19619 in high-fat diet-fed mice significantly improves hepatic glucose and lipid metabolism. Mechanistically, Gm19619 is enriched along genomic regions encoding leptin receptor (Lepr) and transcription factor Foxo1, as revealed in chromatin isolation by RNA purification (ChIRP) assay and is confirmed to modulate their transcription in the mouse liver. In conclusion, Gm19619 may enhance gluconeogenesis and lipid accumulation in the liver.
| S-EPMC9883214 | biostudies-literature
Project description:Backgroundn-3 polyunsaturated fatty acids (PUFA) have previously been demonstrated in association with a reduced risk of chronic diseases, including insulin resistance, cancer and cardiovascular disease. In the present study, we analyzed the effects of n-3 PUFA-rich perilla oil (PO) and fish oil (FO) high fat diet intervention against the synthesis of hepatic high-density lipoprotein cholesterol (HDL-c) in obesity-insulin resistance model rats.MethodsIn the modeling period, the male SD rats were randomly divided into 2 groups. The rats in the high fat (HF) group were given a high fat pure diet containing 20.62% lard. In the intervention period, the model rats were intervened with purified high-fat diets rich in PO or FO, containing same energy content with high fat pure diet in HF. After the intervention, the protein and mRNA expressions status of the key genes involved in synthesis of hepatic HDL-c were measured for further analytic comparison.ResultsThe obesity-insulin resistance model rats were characterized by surprisingly high levels of serum triglyceride (TG) and increased body weight (P < 0.05, each). After the intervention, there were no apparent changes in the serum HDL-c and total cholesterol (TCH). In addition, the FO could up-regulate the hepatic adenosine triphosphate (ATP) binding cassette transporter A1 (ABCA1) mRNA (P < 0.01) and protein expressions, as well as increase the level of serum apolipoprotein A-1 (apoA-1) (P < 0.0001), and elevate the hepatic apoA-1mRNA expression (P < 0.01). Different from FO, the PO specifically elevated the hepatic ABCA1mRNA expression (P < 0.01).ConclusionsThe FO high fat diets promoted the synthesis of HDL-c in the obesity-insulin resistance rats.
| S-EPMC4840880 | biostudies-literature
Project description:The question whether fatty acids can be converted into glucose in humans has a long standing tradition in biochemistry, and the expected answer is "No". Using recent advances in Systems Biology in the form of large-scale metabolic reconstructions, we reassessed this question by performing a global investigation of a genome-scale human metabolic network, which had been reconstructed on the basis of experimental results. By elementary flux pattern analysis, we found numerous pathways on which gluconeogenesis from fatty acids is feasible in humans. On these pathways, four moles of acetyl-CoA are converted into one mole of glucose and two moles of CO₂. Analyzing the detected pathways in detail we found that their energetic requirements potentially limit their capacity. This study has many other biochemical implications: effect of starvation, sports physiology, practically carbohydrate-free diets of inuit, as well as survival of hibernating animals and embryos of egg-laying animals. Moreover, the energetic loss associated to the usage of gluconeogenesis from fatty acids can help explain the efficiency of carbohydrate reduced and ketogenic diets such as the Atkins diet.
| S-EPMC3140964 | biostudies-literature
Project description:ObjectiveIntestinal lipoprotein production has recently been shown to be increased in insulin resistance, but it is not known whether it is regulated by insulin in humans. Here, we investigated the effect of acute hyperinsulinemia on intestinal (and hepatic) lipoprotein production in six healthy men in the presence and absence of concomitant suppression of plasma free fatty acids (FFAs).Research design and methodsEach subject underwent the following three lipoprotein turnover studies, in random order, 4-6 weeks apart: 1) insulin and glucose infusion (euglycemic-hyperinsulinemic clamp) to induce hyperinsulinemia, 2) insulin and glucose infusion plus Intralipid and heparin infusion to prevent the insulin-induced suppression of plasma FFAs, and 3) saline control.ResultsVLDL1 and VLDL2-apoB48 and -apoB100 production rates were suppressed by 47-62% by insulin, with no change in clearance. When the decline in FFAs was prevented by concomitant infusion of Intralipid and heparin, the production rates of VLDL1 and VLDL2-apoB48 and -apoB100 were intermediate between insulin and glucose infusion and saline control.ConclusionsThis is the first demonstration in humans that intestinal apoB48-containing lipoprotein production is acutely suppressed by insulin, which may involve insulin's direct effects and insulin-mediated suppression of circulating FFAs.
| S-EPMC2828667 | 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
Project description:In nonalcoholic fatty liver disease (NAFLD), triglycerides accumulate within the liver because the rates of fatty acid accrual by uptake from plasma and de novo synthesis exceed elimination by mitochondrial oxidation and secretion as very low-density lipoprotein (VLDL) triglycerides. Thioesterase superfamily member 2 (Them2) is an acyl-coenzyme A (CoA) thioesterase that catalyzes the hydrolysis of fatty acyl-CoAs into free fatty acids plus CoASH. Them2 is highly expressed in the liver, as well as other oxidative tissues. Mice globally lacking Them2 are resistant to diet-induced obesity and hepatic steatosis, and exhibit improved glucose homeostasis. These phenotypes are attributable, at least in part, to roles of Them2 in the suppression of thermogenesis in brown adipose tissue and insulin signaling in skeletal muscle. To elucidate the hepatic function of Them2, we created mice with liver-specific deletion of Them2 (L-Them2-/- ). Although L-Them2-/- mice were not protected against excess weight gain, hepatic steatosis or glucose intolerance, they exhibited marked decreases in plasma triglyceride and apolipoprotein B100 concentrations. These were attributable to reduced rates of VLDL secretion owing to decreased incorporation of plasma-derived fatty acids into triglycerides. The absence of hepatic steatosis in L-Them2-/- mice fed chow was explained by compensatory increases in rates of fatty acid oxidation and by decreased de novo lipogenesis in high fat-fed mice. Consistent with a role for Them2 in hepatic VLDL secretion, THEM2 levels were increased in livers of obese patients with NAFLD characterized by simple steatosis. Conclusion: Them2 functions in the liver to direct fatty acids toward triglyceride synthesis for incorporation into VLDL particles. When taken together with its functions in brown adipose and muscle, these findings suggest that Them2 is a target for the management of NAFLD and dyslipidemia.
| S-EPMC6551314 | biostudies-literature