Yasushi Imamura

Animal model of systemic carnitine deficiency: Analysis in C3H-H-2° strain of mouse associated with juvenile visceral steatosis

Abstract We analyzed carnitine profiles in C3H-H-2° strain of mouse associated with fatty liver, hyperammonemia and hypoglycemia (Koizumi et al., 1988). Carnitine levels in serum, liver and muscle of mouse with fatty liver were markedly decreased in comparison with those of control mouse (littermates without fatty liver). This is a useful animal model to analyze the role of carnitine in lipid, amino acid and carbohydrate metabolism.

Factors that predict intrahepatic recurrence of hepatocellular carcinoma in 81 patients initially treated by percutaneous ethanol injection

In Japan, where liver transplantation has not been used to treat patients with hepatocellular carcinoma (HCC), percutaneous ethanol injection (PEI) has been employed for those with small HCCs that are not amenable to surgical resection. In the current study, the authors evaluated PEI as a treatment for HCC patients by studying recurrence rates and survival after treatment. They then examined the clinicopathologic factors that predicted patterns of local and distant intrahepatic recurrence.

Abnormal expression of urea cycle enzyme genes in juvenile visceral steatosis (jvs) mice

Juvenile visceral steatosis (jvs) mice from the C3H-H-2 degrees strain have markedly low levels of all the hepatic urea cycle enzymes (Imamura et al. (1990) FEBS Lett. 260, 119-121). The steady state levels of messenger RNA for the four urea cycle enzymes examined and also for albumin and serine dehydratase were severely reduced in the liver. The levels of mRNA for other liver-specific enzymes including aldolase B and phospho enol pyruvate carboxykinase did not vary significantly from normal littermates. As for extrahepatic expression of the urea cycle enzymes, only argininosuccinate synthetase in the kidney was decreased. Nuclear run-on experiments showed reduced transcription of the corresponding genes, which mostly accounts for the low mRNA levels. Furthermore, the time-course of mRNA accumulation from 5 days of age showed that the developmental induction of hepatic carbamyl phosphate synthetase and argininosuccinate synthetase mRNAs was strongly suppressed. These results suggest that jvs affects not only the regulation of the tissue-specific expression of the urea cycle enzymes but also the regulation of their developmental induction.

Branched-chain amino acids supplements in the late evening decrease the frequency of muscle cramps with advanced hepatic cirrhosis

Eight outpatients with advanced hepatic cirrhosis were tested over 3 months for branched-chain amino acids (BCAA) supplements in the late evening. Serum albumin level (2.8+/-0.3 vs. 3.1+/-0.2 g/dl, P<0.002), serum cholin esterase activity (54+/-13 vs. 67+/-17 IU/l, P<0.02), and plasma Fischers ratio (1.3+/-0.9 vs. 1.4+/-0.9, P<0.005) increased over the 3 months. The frequency of muscle cramps decreased (7.4+/-2.0 vs. 0.3+/-0.5 times/week, P<0.0001) dramatically. These data suggest that BCAA supplements in the late evening are of benefit to malnourished patients with hepatic cirrhosis. Relief of muscle cramping is an important outcome of BCAA supplements in the late evening.

Level of translatable messenger RNA coding for argininosuccinate synthetase in the liver of the patients with quantitative-type citrullinemia

SummaryThe translation activity of mRNA coding for argininosuccinate synthetase in total RNA extracted from the liver of three patients with quantitative-type citrullinemia was determined using a cell-free translation system. In two patients, the hepatic content of the enzyme was about 20% of the control value, whereas translatable mRNA level for the enzyme was similar to or slightly lower than those of control livers. In the third patient, the enzyme content was about 50% of the control value, and mRNA activity for the enzyme was low normal. These results indicate that at least in the first two patients, the decrease in the enzyme protein is due either to increased degradation of the enzyme or to decreased translation in the patients liver.

Abnormal gene expression and regulation in the liver of jvs mice with systemic carnitine deficiency

Carnitine-deficient jvs mice expressed reduced levels of a group of genes which are preferentially expressed in the liver, including urea cycle enzyme genes (Biochim. Biophys. Acta 1138, 167-171, 1992). The expression of alpha-fetoprotein and aldolase A was elevated, indicating that the liver of jvs mice is undifferentiated or dedifferentiated (FEBS Lett. 311, 63-66, 1992). Studies of the hormone signal transduction pathway showed that serum cortisol and plasma glucagon levels of jvs mice were 2 and 3 times higher, respectively, than those of normal mice, and that the hormone binding activity of glucocorticoid receptor (GR) in the cytosol of jvs liver was 50% of normal mice, which reflected the amount of receptor protein in the cytosol. On the other hand, GR protein accumulated in the nuclear fraction in jvs mice. Exogenously administrated dexamethasone induced carbamoyl phosphate synthetase (CPS) and tyrosine aminotransferase (TAT) mRNAs in jvs mice, indicating that CPS and TAT genes in jvs mice are responsive to induction by glucocorticoid and cAMP. Analysis of transacting factors by gel retardation assay revealed that HNF-1, COUP-TF and SP-1 were detected at almost the same level in the hepatic nuclear fraction of jvs mice as in normal littermates, and C/EBP and CREB were a little higher in jvs mice, suggesting that these factors are probably not targets of jvs mutation causing abnormal gene expression in the liver. On the other hand, AP-1 binding activity was much higher in jvs mice from an early age, preceding the abnormal expression of urea cycle enzyme, and carnitine administration normalized AP-1 binding activity. We suggest that elevated AP-1 binding induced by carnitine deficiency is closely connected with the abnormal gene expression in the liver.

Carbamoylphosphate synthetase deficiency in an adult: Deterioration due to administration of valproic acid

SummaryA 24-year-old patient had symptoms of lethargy, convulsions and hyperammonaemia during valproic acid therapy. Cessation of valproic acid treatment brought about an improvement both of the symptoms and of the hyperammonaemia. However, enzymatic analysis after the cessation of valproic acid therapy revealed a complete absence of carbamoylphosphate synthetase (CPS) activity in liver biopsy. A unique polypeptide band, corresponding to the control CPS protein in molecular weight (‘CPS-like’ protein), was found in normal amounts in the patients liver on sodium dodecyl sulphate-polyacrylamide gel electrophoresis. This CPS-like protein seemed to be more labile than the control, because the polypeptide band became faint after freeze-thawing. Intravenous administration ofl-alanine resulted in a significant increase of serum urea and a transient increase of blood ammonia concentrations. These results strongly suggest that the patient has a labile CPS protein with no activityin vitro but some activityin vivo. We consider that valproic acid may have disrupted some metabolic adaptation by reducingN-acetylglutamate in the liver, which in combination with CPS deficiency induced severe hyperammonaemia.

Association between changes in body composition and the increasing prevalence of fatty liver in Japanese men.

Aim:  Prevalence of fatty liver is increasing. In this study, to elucidate the factor that contributes most to recent increases in prevalence of fatty liver, we determined the independent predictors for the onset of fatty liver and compared these predictors between 2000 and 2005.

Fatty liver in men is associated with high serum levels of small, dense low-density lipoprotein cholesterol.

AimsOur study addressed potential associations between fatty liver and small, dense low-density lipoprotein cholesterol (sd-LDL-C) levels using a cross-sectional analysis.MethodsWe enrolled 476 male subjects. Serum sd-LDL-C concentrations were determined using precipitation assays.ResultsSubjects were divided into four groups based on triglyceride (TG) and LDL-C levels: A, TG < 150 mg/dl and LDL-C < 140 mg/dl; B, TG < 150 mg/dl and LDL-C ≥ 140 mg/dl; C, TG ≥ 150 mg/dl and LDL-C < 140 mg/dl; and D, TG ≥ 150 mg/dl and LDL-C ≥ 140 mg/dl. sd-LDL-C levels and the prevalence of fatty liver were significantly higher in groups B, C, and D than in group A. Subjects were also categorized into four groups based on serum sd-LDL-C levels; the prevalence of fatty liver significantly increased with increasing sd-LDL-C levels. Additionally, logistic regression analysis revealed an independent association between sd-LDL-C concentrations and fatty liver using such potential confounders as obesity and hyperglycemia as variables independent of elevated TG or LDL-C levels.ConclusionsFatty liver is a significant determinant of serum sd-LDL-C levels independent of the presence of obesity or hyperglycemia. Fatty liver may alter hepatic metabolism of TG and LDL-C, resulting in increased sd-LDL-C levels.

Efficacy of vasopressin V2 receptor antagonist tolvaptan in treatment of hepatic edema

Tolvaptan, an oral active vasopressin V2 receptor antagonist, is widely used for hepatic edema in Japan, but its clinical benefits have yet to be fully clarified. The present study evaluated the efficacy of tolvaptan in hepatic edema.