Impaired ketogenesis is a major mechanism for disturbed hepatic fatty acid metabolism in rats with long-term cholestasis and after relief of biliary obstruction

Lang, Corinne; Berardi, Simona; Schäfer, Markus; Serra, Dolors; Hegardt, Fausto G.; Krähenbühl, L.; Krähenbühl, Stephan

doi:10.1016/s0168-8278(02)00248-9

Cited by 17 publications

(11 citation statements)

References 31 publications

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“…In addition, serum TG concentration was decreased on day 14 in the PB-treated rats, which agreed with a previous report (Venkatesan et al 1994), indicating an enhanced hydrolysis of TG and fatty acid generation (Teusink et al 2003). Taking all these data together, it was suggested that synthesis of HMG-CoA, which is used for cholesterogenesis and ketone body synthesis (Hettema and Tabak 2000;Horton et al 2002;Lang et al 2002;Millatt et al 2003), was stimulated following a supply of acetyl-CoA generated from lipolysis. To examine the assumption, we next investigated gene expression in rat livers.…”

Section: Discussionsupporting

confidence: 90%

Molecular mechanism investigation of phenobarbital-induced serum cholesterol elevation in rat livers by microarray analysis

Kiyosawa¹,

Tanaka²,

Hirao³

et al. 2004

Arch Toxicol

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Phenobarbital (PB) increases serum total cholesterol levels in rodents and humans. To investigate the underlying molecular mechanisms, we performed a microarray analysis on liver of rats treated repeatedly with 100 mg/kg PB, and examined the serum blood chemistry. The serum concentration of non-esterified fatty acids was decreased from day 1 to day 14 except for day 7, and that of cholesterol was increased from day 4 to day 14. The serum concentration of total ketone bodies was increased on day 7, and that of triglycerides was decreased on day 14. Transcript content of glycolytic genes was decreased by PB treatments, while that of lipoprotein lipase was continuously increased, suggesting a notion that repetitive PB treatments impaired glycolysis and stimulated lipolysis in the liver. The hypothesis was examined by using a previously reported flux-balance model. The increase in mRNA content of malic enzyme after the PB treatment agreed well with the flux-balance model result, suggesting the validity of our hypothesis. The findings also suggested that there was an abundance of acetyl-CoA and shortage of glycolytic products after the repeated PB treatments. Although ketogenesis would normally occur under such cellular conditions, it was only weakly observed after the repeated PB treatments, presumably owing to a decrease in HMG-CoA synthase mRNA content. On the other hand, the mRNA content of several cholesterogenic genes was slightly induced by PB treatments. Thus, serum chemistry and microarray results suggested that repeated PB treatments induced cholesterogenesis in rat livers, which may have contributed to the elevation of the serum total cholesterol concentration.

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Section: Discussionsupporting

confidence: 90%

Molecular mechanism investigation of phenobarbital-induced serum cholesterol elevation in rat livers by microarray analysis

Kiyosawa¹,

Tanaka²,

Hirao³

et al. 2004

Arch Toxicol

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“…It also shows that exercise training will normalize plasma FFA levels and markedly reduce ␤-hydroxybutyric acid levels in these diabetic rats. Furthermore, exercise training also decreases hepatic ketone body synthesis measured as the activity of the HMG-CoA, a rate-limiting enzyme in hepatic ketogenesis (10).…”

Section: Discussionmentioning

confidence: 99%

Physical training reverses the increased activity of the hepatic ketone body synthesis pathway in chronically diabetic rats

Midaoui¹,

Chiasson²,

Tancrède³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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This study was designed to examine whether the training-induced improvement in the plasma concentration of ketone bodies in experimental diabetes mellitus could be explained by changes in the activity of the hepatic ketone body synthesis pathway and/or the plasma free fatty acid levels. Diabetes mellitus was induced by an intravenous injection of streptozotocin (50 mg/kg), and training was carried out on a treadmill. The plasma concentration of ␤-hydroxybutyric acid was increased (P Ͻ 0.001) in sedentary diabetic rats, and this was partly reversed by training (P Ͻ 0.001). The plasma concentration of free fatty acids was increased (P Ͻ 0.001) in sedentary diabetic rats, and this was reversed to normal by training (P Ͻ 0.001). Diabetes was also associated with an increased activity of the hepatic ketone body synthesis pathway. When the data are expressed as per total liver, physical training decreased the activity of the hepatic ketone body synthesis pathway by 18% in nondiabetic rats (P Ͻ 0.05) and by 22% in diabetic rats (P Ͻ 0.01), the activity present in trained diabetic rats being not statistically different from that of sedentary control rats. These data suggest that the beneficial effects of physical training on the plasma ␤-hydroxybutyric acid levels in the diabetic state are probably explained in part by a decrease in the activity of the hepatic ketone body synthesis pathway and in part by a decrease in plasma free fatty acid levels.

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“…The S-nitrosation of critical mitochondrial enzymes participating in ATP synthesis and fatty acid metabolism may explain the mitochondrial dysfunction and the disturbed fatty acid metabolism associated with cholestasis. 43,44 It can be noted that two of the other identified proteins are important enzymes involved in the methionine cycle, namely, BHMT and AdoMet synthetase, also known as methionine adenosyltransferase (MAT). The inhibition of hepatic BHMT causes hyperhomocysteinemia, 45 a condition that has been recently shown to be involved in hepatic fibrosis 46 and is observed in primary billiary cirrhosis 47 and obstructive cholestasis.…”

Section: Protein S-nitrosation During Cholestasismentioning

confidence: 99%

Inhibition of nitric oxide synthesis during induced cholestasis ameliorates hepatocellular injury by facilitating S-nitrosothiol homeostasis

López‐Sánchez

Corrales

Barcos

et al. 2010

Laboratory Investigation

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Cholestatic liver injury following extra-or intrahepatic bile duct obstruction causes nonparenchymal cell proliferation and matrix deposition leading to end-stage liver disease and cirrhosis. In cholestatic conditions, nitric oxide (NO) is mainly produced by a hepatocyte-inducible NO synthase (iNOS) as a result of enhanced inflow of endotoxins to the liver and also by accumulation of bile salts in hepatocytes and subsequent hepatocellular injury. This study was aimed to investigate the role of NO and S-nitrosothiol (SNO) homeostasis in the development of hepatocellular injury during cholestasis induced by bile duct ligation (BDL) in rats. Male Wistar rats (200-250 g) were divided into four groups (n ¼ 10 each), including sham-operated (SO), bile duct-ligated (BDL), tauroursodeoxycholic acid (TUDCA, 50 mg/kg) and S-methylisothiourea (SMT, 25 mg/kg) treated. After 7 days, BDL rats showed elevated serum levels of g-glutamiltranspeptidase, aspartate aminotransferase, alanine aminotransferase, LDH, and bilirubin, bile duct proliferation and fibrosis, compared with the SO group. TUDCA treatment did not significantly alter these parameters, but the iNOS inhibitor SMT ameliorated hepatocellular injury, as shown by lower levels of circulating hepatic enzymes and bilirubin, and a decreased grade of bile duct proliferation and fibrosis. Both TUDCA and SMT treatments reversed Mrp2 canalicular pump expression to control levels. However, only SMT treatment significantly lowered the increased levels of plasma NO and S-nitrosation (S-nitrosylation) of liver proteins in BDL rats. Moreover, BDL resulted in a reduction of the S-nitrosoglutathione reductase (GSNOR/Adh5) enzymatic activity and a downregulation of the GSNOR/Adh5 mRNA expression that was reverted by SMT, but not TUDCA, treatment. A total of 25 liver proteins, including S-adenosyl methionine synthetase, betainehomocysteine S-methyltransferase, Hsp90 and protein disulfide isomerase, were found to be S-nitrosated in BDL rats. In conclusion, the inhibition of NO production during induced cholestasis ameliorates hepatocellular injury. This effect is in part mediated by the improvement of cell proficiency in maintaining SNO homeostasis.

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Impaired ketogenesis is a major mechanism for disturbed hepatic fatty acid metabolism in rats with long-term cholestasis and after relief of biliary obstruction

Cited by 17 publications

References 31 publications

Molecular mechanism investigation of phenobarbital-induced serum cholesterol elevation in rat livers by microarray analysis

Molecular mechanism investigation of phenobarbital-induced serum cholesterol elevation in rat livers by microarray analysis

Physical training reverses the increased activity of the hepatic ketone body synthesis pathway in chronically diabetic rats

Inhibition of nitric oxide synthesis during induced cholestasis ameliorates hepatocellular injury by facilitating S-nitrosothiol homeostasis

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