Fuel homeostasis and carnitine metabolism in rats with secondary biliary cirrhosis

Abstract

Energy metabolism is abnormal in patients and experimental animals with liver cirrhosis. To help better understand the abnormalities, fuel homeostasis and carnitine metabolism were studied in fed and 24-hr-starved rats with secondary biliary cirrhosis induced by bile duct ligation for 4 wk. Plasma ketone body concentrations were decreased by 67% in starved, bile duct-ligated rats compared with control rats. In contrast, plasma nonesterified fatty acid concentrations were not different between bile duct-ligated and control rats in the fed or the fasted state. Plasma triglyceride concentrations showed the expected decrease with starvation in control rats, but were increased with starvation in bile duct-ligated rats. Urinary excretion of dicarboxylic acids was increased in both fed and fasted bile duct ligated-rats compared with the respective control groups. Compared with control rats, hepatic total carnitine content (per gram of liver) was increased by 24% in fed and by 36% in fasted, bile duct-ligated rats. Fed, bile duct-ligated rats had an increased short-chain acylcarnitine-to-carnitine ratio in liver, plasma and urine compared with control rats. Analysis of the hepatic coenzyme A pool showed decreased coenzyme A content in fed and fasted bile duct-ligated rats compared with control rats. Hepatic long-chain acylcarnitine and long-chain acyl-coenzyme A content increased with starvation both in control and bile duct-ligated rats. The rise in plasma nonesterified fatty acid concentration and hepatic long-chain acylcarnitine and long-chain acylcoenzyme A contents with starvation in bile duct-ligated rats are consistent with unaltered hepatic availability of fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased carnitine biosynthesis in rats with secondary biliary cirrhosis

“…Similar increases in the hepatic total carnitine and acylcarnitine contents have been reported in rats with long-term BDL fed normal rat food. 25,26 Skeletal muscle long-chain acylcarnitine content was increased 2-fold in BDL rats as compared with control rats, but there was no difference in the contents of free carnitine, short-chain acylcarnitine, or total skeletal muscle carnitine between the 2 groups. In contrast to tissue carnitine content, NOTE.…”

“…11 After an acclimation period of 2 weeks, rats were randomized into 2 groups. Rats in the first group (n ϭ 10) were bile duct-ligated 25 (ligation and transection of the common bile duct) under ketamine anesthesia (10 mg/100 g body weight intraperitoneally). Three sutures were placed around the common bile duct approximately 3 cm (first suture) and 5 cm from the duodenum (second and third sutures).…”

“…24 Rats with secondary biliary cirrhosis induced by long-term bile duct ligation (BDL) have increased hepatic carnitine content with a shift in the ratio of acylcarnitines/carnitine toward acylcarnitines in the fed state. 25,26 These changes in the hepatic carnitine pool are accompanied by an increase in urinary acylcarnitine excretion, whereas the total carnitine excretion is unchanged during feeding of a carnitinecontaining diet. 25 Because the metabolic changes observed in BDL rats are similar to those described in patients with cirrhosis, [21][22][23] BDL rats provide a model to approach the divergent views in the literature outlined above concerning carnitine biosynthesis in cirrhosis.…”

“…25,26 These changes in the hepatic carnitine pool are accompanied by an increase in urinary acylcarnitine excretion, whereas the total carnitine excretion is unchanged during feeding of a carnitinecontaining diet. 25 Because the metabolic changes observed in BDL rats are similar to those described in patients with cirrhosis, [21][22][23] BDL rats provide a model to approach the divergent views in the literature outlined above concerning carnitine biosynthesis in cirrhosis. The specific aims of the current studies were therefore: 1) to characterize carnitine biosynthesis in rats with long-term BDL; and 2) to discover the mechanisms involved in the expected changes in carnitine biosynthesis in this animal model of cirrhosis.…”

Plasma and hepatic carnitine and coenzyme A pools in a patient with fatal, valproate induced hepatotoxicity.

“…Interestingly, the total CoA content in livers from rats with secondary biliary cirrhosis, an animal model of chronic liver disease with impaired hepatic fatty acid metabolism,43 was also found to be decreased. 39 On the other hand, the hepatic coenzyme A pool in rats with carbon tetrachloride induced liver cirrhosis was not different from control rats (S Krahenbuihl and E Brass, unpublished data), showing that the cause of liver disease is important for the induction of changes in the CoA pool. As CoASH is a critical substrate for P-oxidation, a decrease in the hepatic CoASH content could lead to impaired hepatic fatty acid metabolism, which is considered to represent the major mechanism in valproate induced hepatotoxicity.5 25 In contrast with the reversible inhibition of hepatic energy metabolism (including fatty acid oxidation), which is normally associated with the administration of valproate to humans or experimental animals,5 32 35-37 41 42 44 fatal hepatic toxicity is rare.2-4 Two factors known to increase the risk of severe hepatic toxicity are concomitant administration of substances inducing hepatic cytochrome P450 isoenzymes and young age.4 Our findings support the concept that reduced hepatic mitochondrial metabolism represents another risk factor for valproate induced hepatotoxicity.28 Our patient was treated with low dose acetylsalicylic acid, a drug known to inhibit hepatic P-oxidation.…”