Carnitine liver

Esser, V., Britton, C.H., Weiss, B.C., Foster, D.W. McGarry, J.D. (1993). Cloning, sequencing and expression of a cDNA encoding rat liver carnitine palmitoyltransferase 1. Direct evidence that a single polypeptide is involved in inhibitor interaction and catalytic function. J. Biol. Chem. 268, 5817-5822. 

After uptake by the liver, free fatty acids are either P Oxidized to COj or ketone bodies or esterified to triacylglycerol and phospholipid. There is regulation of entry of fatty acids into the oxidative pathway by carnitine palmitojdtransferase-I (CPT-I), and the remainder of the fatty acid uptake is esterified. CPT-I activity is... 

Faye, A., Esnous, C., Price, N.T., Onfray, M.A., Girard, J., and Prip-Buus, C. (2007) Rat liver carnitine palmitoyltransferase 1 forms an oligomeric complex within the outer mitochondrial membrane.. Biol. Cbem. 10.1074/jbc.M705418200. 

Special diet low in isoleucine, valine, methionine, threonine. Carnitine supplementation. Liver transplantation may be beneficial. 

Two studies were located in which rats received di- -octylphthalate dietary exposures of 250 or 500 mg/kg/day for either 10 or 26 weeks (Carter et al. 1992 DeAngelo et al. 1986). Five male rats were first initiated with a single subcarcinogenic intraperitoneal dose of diethylnitrosamine (30 mg/kg), followed by partial hepatectomy. Di-w-octylphthalatc caused substantial increases in gamma-glutamyltranspeptidase (GGT) positive liver foci when compared with the controls (e.g., from 3.5 to 20.8 foci/cm2) or in hepatic levels of marker enzymes for altered cellular foci (GGT and glutathione 5-transferase [GST]). Only a slight increase (threefold) was observed for carnitine acetyltransferase (CAT) activity, a marker for peroxisome... 

Carnitine Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH]... 

Carnitine deficiency leads to impaired carnitine shuttle activity the resulting decreased LCFA metabolism and accumulation of LCFAs In tissues and wasting of acyl-carnitine in urine can produce cardiomyopathy, skeletal muscle myopathy, encephalopathy, and impaired liver function. 

The answer is D. The most likely diagnosis in this case is CPT-II deficiency, although this is apparently a fairly mild case. The patient s muscle weakness and brown urine (myoglobinuria) are characteristic of this disorder. CPT-I deficiency would most likely manifest as liver dysfunction. A secondary form of carnitine deficiency due to exogenous factors such as malnutrition, infection, or dialysis, is unlikely. MCAD ordinarily manifests within the first 3-5 years of life. The patient s normal stature is inconsistent with Marfan syndrome, which is characterized by tall stature and very long bones in the extremities. 

Ascorbic acid or vitamin C is found in fruits, especially citrus fruits, and in fresh vegetables. Man is one of the few mammals unable to manufacture vitamin C in the liver. It is essential for the formation of collagen as it is a cofactor for the conversion of proline and lysine residues to hydroxyproline and hydroxylysine. It is also a cofactor for carnitine synthesis, for the conversion of folic acid to folinic acid and for the hydroxylation of dopamine to form norepinephrine. Being a lactone with two hydroxyl groups which can be oxidized to two keto groups forming dehydroascorbic acid, ascorbic acid is also an anti-oxidant. By reducing ferric iron to the ferrous state in the stomach, ascorbic acid promotes iron absorption. 

Male Fischer 344 rats (body weight, 100-150 g) were fed 0.5-4% di(2-ethyl-hexyl) phthalate in the diet for one or four weeks and male Swiss Webster mice (20-30 g) were fed 2 or 4% di(2-ethylhexyl) phthalate in the diet for one or four weeks (Reddy etal., 1976). Di(2-ethylhexyl) phthalate increased relative liver weights and markedly induced hepatic carnitine acetyltransferase activity in both species (up to 25-fold in rats and 10-fold in mice). Some increase in hepatic catalase activity (approximately two-fold) was observed and subjective (non-morphometric) ultra-structural examination revealed marked peroxisome proliferation. This study also demonstrated that di(2-ethylhexyl) phthalate was a hypolipidaemic agent, as serum triglyceride levels were reduced to one seventh of control values in rats and one third of control values in mice. 

Hepatocytes were isolated from male Fischer 344 rats and from two human liver samples (liver surgery patients). Treatment with 200 pM mono(2-ethylhexyl) phthalate for either 48 or 72 h induced carnitine acetyltransferase activity in cultured rat but not human hepatocytes (Butterworth et al, 1989). 

Normal persons excrete very little TMA in the urine. However, slight TMA excretion may be observed after meals with a high content of TMA precursors like choline or lecithin, or after eating marine fish due to its high TMA N-oxide content. Healthy women may have a short episode of trimethylaminuria at the onset and during menstruation. TMA has also found to be increased in the urine of some patients using carnitine supplementation. Advanced liver and renal disease may result in TMA excretion and this constitutes the so-called secondary trimethylaminurias. 

The incidence of the severe form is between 1 in 20,000 and 1 in 40,000 in adults, although the incidence is much higher in children (1 in 5000). The fatty liver is a "visible" symptom of dysfunction, not necessarily a cause of liver failure, although it can be. Valproic acid is similar to a fatty acid and therefore can become incorporated into fatty acid metabolism. This involves formation of an acyl CoA derivative and also a carnitine derivative. However, this depletes both CoA from the intramitochondrial pool and carnitine and so compromises the mitochondria and reduces the ability of the cell to metabolize short-, medium-, and long-chain fatty acids via p-oxidation (Fig. 7.15). 

Participation as a cofactor in an number of enzymatic reactions, including the synthesis of collagen, carnitine, and norepinephrine the metabolism of tryptophan, tyrosine, histamine, and cholesterol the amidation of neuropeptides and detoxification reactions in the liver... 

Carnitine deficiency in liver is correlated with hypoglycemia. Suggest a plausible explanation for hypoglycemia in the carnitine-deficient human. 

A 37-year-old HIV-infected woman receiving stavudine, lamivudine, and indinavir developed epigastric pain, anorexia, and vomiting. She had lactic acidosis (serum lactate 4.9 mmol/1), raised liver enzymes, and an increased prothrombin time. She had hepatomegaly and tachypnea and required mechanical ventilation. Her progress was complicated by pancreatitis and acute respiratory distress syndrome. Antiviral medication was stopped and she was treated with co-enzyme Q, carnitine, and vitamin C. The serum lactic acid and transaminases returned to normal over 4 weeks and she was weaned off the ventilator after 4 months. 

Rat (Sprague- Dawley) 5 d 1x/d (GO) Hepatic 10 100 (increased liver weight and activity of palmitoyl CoA oxidase and carnitine acetyl transferase) Dostal et al. 1987a ... 

Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to DEHP. Limited information on hepatic effects in humans exposed to DEHP is available from studies of dialysis patients and cultured human hepatocytes. In one individual there was an increased number of liver peroxisomes after 1 year, but not after 1 month of treatment (Ganning et al. 1984, 1987). A serious limitation of this observation is that repeat biopsies were not obtained from the same patient, so that an appropriately controlled analysis is not possible. Additionally, analysis of liver biopsies from patients receiving other kinds of hypolipidemic drugs has not yielded any evidence for peroxisomal proliferation (Doull et al. 1999). Recognizing some limitations of using primary hepatocytes in vitro because of their tendency to lose some metabolic capabilities (Reid 1990), in cultured human hepatocytes there were no changes in the activities of peroxisomal palmitoyl-CoA oxidase and/or carnitine acetyltransferase when... 

Glucagon exerts a ketogenic action on the liver which is more pronounced in insulin-deficient states. This action is thought to be due mainly to the inhibition of acetyl-CoA carboxylase with resulting decrease in malonyl-CoA. Malonyl-CoA is an inhibitor of carnitine acyltransferase I which is the rate-limiting step for mitochondrial fatty acid oxidation. A decrease in malonyl-CoA is thus postulated to lead to overproduction of acetyl-CoA which is then condensed to form ketone bodies. 

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