Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia
Anfal Al‐MassPegah PoursharifiMarie‐Line PeyotRoxane LussierIsabelle ChénierYat Hei LeungAnindya GhoshAbel OppongElite PossikYves MugaboRasheed AhmadRobert SladekS.R. Murthy MadirajuFahd Al‐MullaMarc Prentki
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Glycerol-3-phosphate (Gro3P) phosphatase (G3PP) hydrolyzes Gro3P to glycerol that exits the cell, thereby operating a "glycerol shunt", a metabolic pathway that we identified recently in mammalian cells. We have investigated the role of G3PP and the glycerol shunt in the regulation of glucose metabolism and lipogenesis in mouse liver. We generated hepatocyte-specific G3PP-KO mice (LKO), by injecting AAV8-TBG-iCre to male G3PPfl/fl mice. Controls received AAV8-TBG-eGFP. Both groups were fed chow diet for 10 weeks. Hyperglycemia (16–20 mM) was induced by glucose infusion for 55 h. Hepatocytes were isolated from normoglycemic mice for ex vivo studies and targeted metabolomics were measured in mice liver after glucose infusion. LKO mice showed no change in body weight, food intake, fed and fasted glycemia but had increased fed plasma triglycerides. Hepatic glucose production from glycerol was increased in fasted LKO mice. LKO mouse hepatocytes displayed reduced glycerol production, elevated triglyceride and lactate production at high glucose concentration. Hyperglycemia in LKO mice led to increased liver weight and accumulation of triglycerides, glycogen and cholesterol together with elevated levels of Gro3P, dihydroxyacetone phosphate, acetyl-CoA and some Krebs cycle intermediates in liver. Hyperglycemic LKO mouse liver showed elevated expression of proinflammatory cytokines and M1-macrophage markers accompanied by increased plasma triglycerides, LDL/VLDL, urea and uric acid and myocardial triglycerides. The glycerol shunt orchestrated by G3PP acts as a glucose excess detoxification pathway in hepatocytes by preventing metabolic disturbances that contribute to enhanced liver fat, glycogen storage, inflammation and lipid build-up in the heart. We propose G3PP as a novel therapeutic target for hepatic disorders linked to nutrient excess.Keywords:
Lipogenesis
Dihydroxyacetone phosphate
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The Kupffer-cell products interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) have been shown to stimulate hepatic lipogenesis in vivo. Studies were performed to define the direct effects of these cytokines on lipogenesis in primary-culture rat hepatocytes. Hepatocytes were cultured in the presence of IL-6 or TNF-alpha for periods of 24-72 h. IL-6 increased hepatocyte protein content per microgram of DNA. IL-6 also caused a dose- and time-dependent induction of hepatocyte capacity for incorporation of [2-14C]pyruvate into fatty acids (56% increase by 12.5 ng/ml IL-6 after 72 h of cytokine exposure). This increase in cellular lipogenic capacity was confirmed by using 3H2O incorporation into fatty acids as tracer. TNF-alpha did not increase hepatocyte lipogenesis. In contrast with studies in vivo, neither IL-6 nor TNF-alpha had any acute (2 h of exposure) effects on rates of lipogenesis. Both IL-6 and TNF-alpha are known to increase macrophage prostaglandin synthesis acutely. The prostaglandin E agonist misoprostol free acid (0.1 microM) acutely increased hepatocyte lipogenic rates by 14%. Thus, IL-6 can directly induce hepatocyte lipogenic capacity, and E-series prostaglandins can antagonize the acute inhibition of lipogenesis by glucagon. The observations provide further evidence for the role of Kupffer-cell products in the regulation of hepatocyte metabolism.
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Abstract Lipogenesis is a vital but often dysregulated metabolic pathway. We report super-resolution multiplexed vibrational imaging of lipogenesis rates and pathways using isotopically labelled oleic acid and glucose as probes in live adipocytes and hepatocytes. These findings suggest oleic acid inhibits de novo lipogenesis (DNL), but not total lipogenesis, in hepatocytes. No significant effect is seen in adipocytes. These differential effects may be due to alternate regulation of DNL between cell types and could help explain the complicated role oleic acid plays in metabolism.
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Dihydroxyacetone phosphate
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This study compared the effects of certain metabolites (either singly or in various combinations) and the methods of measuring lipogenesis (using either 14C-acetate or 3H2O incorporation into lipids) on total lipid synthesis and insulin-stimulated total lipid synthesis in the isolated rat hepatocyte. There were quantitative and qualitative differences between 14C-acetate and 3H2O incorporation into lipids; metabolites acutely affected both lipogenesis and insulin-stimulated lipogenesis with either isotope; and insulin's effect on lipogenesis was greater when measured by 14C-acetate incorporation. It is suggested that a particular choice of incubation media and isotope may inadvertently bias a study of insulin-stimulated lipogenesis and that metabolite supply plays a major role in regulating insulin-stimulated lipogenesis.
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The current study was undertaken to investigate he effects of human growth hormone(hGH) and porcine GH(pGH) on lipogenesis of adipose tissues from the rats and growing pigs. For the measurement of lipogenesis, epididymal fat tissue was taken from the rats after being killed and for the same purpose the backfat tissue was biopsyed from the pigs. Lipogenesis was determined by the amount of glucose converted to the total lipid. Initially, we investigated the effects of incubation time and glucose concentration on lipogenesis of the epididymal fat tissue of the rats for establishing the optimum condition. The results showed that lipogenesis was linearly increased as the incubation time increased (40, 80 and 120 min) and the total amount of lipogenesis was the same between 5mM and 20mM glucose in the KRB buffer. In in vitro study, adipose tissues were exposed to the varying concentrations of hGH during 48h culture; before the tissues were incubated in the KRB buffer for lipogenesis measurement. Human growth hormone added into the adipose tissue culture did not affect the lipogenesis of epididymal fat tissue of the rats. In in vivo study where the rats were injected daily with 200㎍ of hGH for 10 days, hGH added into the epididymal fat tissue culture did not affect the lipogenesis either. However, pGH as well as hGH contained in the culture media decreased the lipogenesis of the adipose tissue from growing pigs in dose-dependent manner. These results indicated that hGH decreased lipogenesis in the pigs, but not in the rats.
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Objective:To investigate the long-term effects of low dosage La(NO3)3 on insulin and blood glucose in serum and hepatocyte glycogen in rat.Methods:Levels of Insulin and blood glucose and hepatocyte glycogen in rat were measured by radiommunoassay and microscopy image analysis system after administrated with La(NO3)3(10.0 mg/kg、 2.0 mg/kg、 0.2 mg/kg、 0.1 mg/kg)for six and seven months.Results:Having taken La(NO3)3 for 6 months,insulin levels in the 10.0 mg/kg group were reduced,blood glucose and hepatocyte glycogen levels in the 10.0 mg/kg group were increased,both in the sera of female and male rats;insulin levels、 blood glucose levels and hepatocyte glycogen levels in the 0.1 mg/kg、 0.2 mg/kg、 2.0mg/kg group,low dose treated groups was increased and later was reduced in the sera of the male.After fed by normal chow without La(NO3)3 for one month,the levels of insulin、 blood glucose and hepatocyte glycogen returned to normal again.Conclusion:A long-term low dosage La(NO3)3 could change insulin、 blood glucose and hepatocyte glycogen levels.Insulin、 blood glucose and hepatocyte glycogen levels could back to normal levels after a short time of feeding without La.La(NO3)3.In concentration of 0.2 mg/kg and 0.1 mg/kg,it had the capacity to increase the levels of insulin、 blood glucose and hepatocyte glycogen.
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The Spot 14 (S14; Thrsp) gene has been implicated in supporting regulated lipogenesis in mammals. S14 gene expression in liver is controlled by a wide variety of hormones and dietary factors in parallel with the major lipogenic enzyme genes. In addition, mice deleted for the S14 gene display reduced de novo lipogenesis in the lactating mammary gland. However, no decrease in hepatic lipogenesis was observed in the S14 null mouse. It was postulated that this difference could be due to the expression of a paralogous gene called S14R (S14 related; Mig12) in the liver but not mammary tissue. To test this hypothesis, we used small interfering RNA to simultaneously reduce levels of S14 and S14R in cultured primary hepatocytes. We found that rates of lipogenesis were decreased by approximately 65% in cells treated with insulin and high glucose. This reduction was associated with a decrease in total liver triacylglycerols and an altered morphology of lipid droplets. Expression of either S14 or S14R gene products was sufficient to fully restore normal lipogenesis. No change in the hepatic expression of other major lipogenic enzyme genes occurred during manipulation of S14 and/or S14R levels. These data support the hypothesis that both S14 and S14R are directly involved in supporting hepatic lipogenesis and that the two proteins play overlapping roles in this process.
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