The Influence of Ethanol-induced Changes of the alpha-Glycerophosphate Level on Hepatic Triglyceride Synthesis.

Fellenius, E.; Bengtsson, Gunnar; Kiessling, K.‐H.

doi:10.3891/acta.chem.scand.27-2893

Cited by 28 publications

(10 citation statements)

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“…Although the lipid accumulation must be due to an imbalance of fatty acid uptake, ␤-oxidation (8, 9), lipogenesis (10), or lipoprotein export (11), we sought to determine exactly how these processes are disturbed. Ideally, such investigations would be done in vivo, but such studies are complicated by the fact that other organs are known to contribute to gluconeogenesis in these animals (6).…”

mentioning

confidence: 99%

Impaired Tricarboxylic Acid Cycle Activity in Mouse Livers Lacking Cytosolic Phosphoenolpyruvate Carboxykinase

Burgess

Hausler

Merritt

et al. 2004

Journal of Biological Chemistry

146

169

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Liver-specific phosphoenolpyruvate carboxykinase (PEPCK) null mice, when fasted, maintain normal whole body glucose kinetics but develop dramatic hepatic steatosis. To identify the abnormalities of hepatic energy generation that lead to steatosis during fasting, we studied metabolic fluxes in livers lacking hepatic cytosolic PEPCK by NMR using 2 H and 13 C tracers. After a 4-h fast, glucose production from glycogenolysis and conversion of glycerol to glucose remains normal, whereas gluconeogenesis from tricarboxylic acid (TCA) cycle intermediates was nearly absent. Upon an extended 24-h fast, livers that lack PEPCK exhibit both 2-fold lower glucose production and oxygen consumption, compared with the controls, with all glucose production being derived only from glycerol. The mitochondrial reductionoxidation (red-ox) state, as indicated by the NADH/ NAD ؉ ratio, is 5-fold higher, and hepatic TCA cycle intermediate concentrations are dramatically increased in the PEPCK null livers. Consistent with this, flux through the TCA cycle and pyruvate cycling pathways is 10-and 40-fold lower, respectively. Disruption of hepatic cataplerosis due to loss of PEPCK leads to the accumulation of TCA cycle intermediates and a nearly complete blockage of gluconeogenesis from amino acids and lactate (an energy demanding process) but intact gluconeogenesis from glycerol (which contributes to net NADH production). Inhibition of the TCA cycle and fatty acid oxidation due to increased TCA cycle intermediate concentrations and reduced mitochondrial red-ox state lead to the development of steatosis. Hepatic phosphoenolpyruvate carboxykinase (PEPCK)1 is a major control point for gluconeogenesis (1). Excess PEPCK expression in mice causes hyperglycemia (2), hyperinsulinemia, and increased glucose turnover (3). Inhibition of PEPCK by pharmaceutical interventions causes hypoglycemia (4) and, as expected, the global ablation of the cytosolic isoform of PEPCK in mice by genetic manipulation results in nonviable offspring (5). Most surprisingly, the liver-specific deletion of cytosolic PEPCK yielded a phenotype that, except during fasting and exercise, was virtually indistinguishable from control mice (5, 6). Even after a 24-h fast, when liver glycogen is depleted and flux through liver PEPCK should be essential to maintain plasma glucose, these animals are euglycemic and glucose turnover is normal. By using NMR spectroscopy and stable isotope tracers, we demonstrated that approximately ϳ60% of whole body glucose production in liver-specific PEPCK knock-out animals is derived from lactate and alanine (6). This suggests that either an alternative route to glucose production that bypasses PEPCK in these livers exists or that the majority of whole body gluconeogenesis is extrahepatic (6). In marked contrast to the minimal impact that the absence of hepatic PEPCK has on systemic glucose kinetics, these mice develop dramatic hepatic steatosis after fasting (6) even though enzymes of the TCA cycle and ␤-oxidation are up-regulated (5) in liver tissue....

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mentioning

confidence: 99%

Impaired Tricarboxylic Acid Cycle Activity in Mouse Livers Lacking Cytosolic Phosphoenolpyruvate Carboxykinase

Burgess

Hausler

Merritt

et al. 2004

Journal of Biological Chemistry

146

169

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“…Glycerol-3-phosphate may also increase triacylglycerol synthesis by directly stimulating the activity of phosphatidate phosphohydrolate (Savolainin & Hassinen, 1978). However, the reported effects of ethanol consumption on hepatic glycerol-3-phosphate concentrations are contradictory with both increased (Fellenius, Bengtsson & Kiessling, 1973) and reduced (Johnson et al, 1971) levels being reported. Also, under most physiological conditions, glycerol-3-phosphate concentrations are not rate limiting in the esterification of fatty acids (Zammit, 1984).…”

Section: Hepatic Glycerolipid Synthesismentioning

confidence: 95%

Pathogenesis of alcoholic hepatic steatosis

Simpson

1996

Addiction Biology

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Chronic alcohol misuse is the most common cause of hepatic steatosis. The accumulation of lipid is reversible with abstinence, but some workers have suggested that the severity of hepatic steatosis predicts the progression with time to alcoholic cirrhosis. Triacylglycerol is the major accumulating lipid and subcellular fractionation and electron microscopy studies have shown accumulation of lipid droplets within the golgi fraction. This is consistent with the reports in both experimental animals and man of reduced hepatic secretion of very low density lipoprotein triacylglycerol which may be secondary to acetaldehyde-induced disruption of the cytoskeletal elements. In addition, hepatic production of triacylglycerol increases, but most studies in animal models suggest that increased triacylglycerol synthesis becomes less important as hepatic lipid accumulates.

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“…The finding that pyruvate and glutamine did not have such an effect points to the possible role of reducing equivalents in mediating the stimulatory effect of gluconeogenic substrates. In fact, Fellenius et aU 21 1 reported the lack of any change in α-glycerophosphate levels after pyruvate administration.…”

Section: The Effect Of Substrates and Ethanolmentioning

confidence: 95%

Regulation of Net Triacylglycerol Synthesis by Metabolic Substrates in Isolated Rat Liver Cells

Wirthensohn¹,

Brocks²,

Guder³

1980

Hoppe-Seyler´s Zeitschrift für physiologische Chemie

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Triacylglycerol metabolism was studied in isolated rat hepatocytes using a fully enzymatic method to measure cellular glyceride-glycerol. With this method 40 and 50 μτηοΐ triacylglycerol were found per g cellular protein in liver cells from fed and starved rats, respectively, comparable to values obtained after organic solvent extraction and alkaline hydrolysis of neutral lipids. Carbohydrate refeeding of animals increased triacylglycerol levels in hepatocytes to 80 μπιοΐ. Upon incubation without fatty acids a 15 % decrease in cellular triacylglycerol was found in 60 min. When ImM oleate or palmitate were added cellular triacylglycerol increased.. The rates of net triacylglycerol synthesis were not significantly different with oleate and palmitate. Starvation reduced the rates from both fatty acids, whereas carbohydrate refeeding led to a marked increase in net triacylglycerol synthesis. Besides 20mM glucose, 5mM L-lactate and 5mM fructose stimulated triacylglycerol synthesis from fatty acids. The stimulatory effect of lactate was higher in hepatocytes from starved animals, so that the differences in triacylglycerol synthesis between liver cells from fed and starved rats were abolished. Fatty acids taken up and not recovered in newly formed triacylglycerol were released as ketone bodies.When radioactive lactate was offered to cells from starved rats, label incorporated into neutral lipids was exclusively recovered from the glycerol moiety of triacylglycerols. 5mM ethanol which alone increased fatty acid esterification, reduced the stimulatory effect of lactate but increased the effect of fructose on net triacylglycerol formation.These findings indicate that esterification rate in liver cells from starved rats can be limited by availability of α-glycerophosphate, which is provided by glyceroneogenesis. The possible physiological significance of these findings is discussed with regard to liver cell heterogeneity and nutritional adaptation of liver triacylglycerol formation. Regulation der Triacylglycerinsynthese in Hepatozyten durch metabolische SubstrateZusammenfassung: Mit einer vollenzymatischen Methode zur Bestimmung von zellul rem Glyceridglycerin wurde der Triacylglycerinstoffwechsel isolierter Hepatozyten der Ratte untersucht. Der Triglyceridgehalt in Leberzellen von gef tterten und hungernden Tieren lag mit dieser Methode bei 40 bzw. 50 μιηοΐ/g Protein. Vergleichbare Werte wurden nach Extraktion mit organischen L sungsmitteln und alkalischer Hydrolyse der Neutrallipide gefunden. Kohlenhydratwieder-

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The Influence of Ethanol-induced Changes of the alpha-Glycerophosphate Level on Hepatic Triglyceride Synthesis.

Cited by 28 publications

References 0 publications

Impaired Tricarboxylic Acid Cycle Activity in Mouse Livers Lacking Cytosolic Phosphoenolpyruvate Carboxykinase

Impaired Tricarboxylic Acid Cycle Activity in Mouse Livers Lacking Cytosolic Phosphoenolpyruvate Carboxykinase

Pathogenesis of alcoholic hepatic steatosis

Regulation of Net Triacylglycerol Synthesis by Metabolic Substrates in Isolated Rat Liver Cells

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