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To further understand the role of lipogenesis and lipotoxicity in the development of obesity and diabetes, lipidomes of various organs from ob/ob mice and their wild type controls were analyzed by shotgun lipidomics at 10, 12, and 16 weeks of age. We observed that the amounts of fatty acyl (FA) chains corresponding to those from de novo synthesis (e.g., 16:0, 16:1, and 18:1 FA) were substantially elevated in ob/ob mice, consistent with increased expression of genes and proteins involved in biosynthesis. Polyunsaturated fatty acid species were moderately increased in the examined tissues of ob/ob mice, since they can only be absorbed from diets or elongated from the ingested n-3 or n-6 FA. Different profiles of FA chains between ob/ob mouse liver and skeletal muscle reflect diverging lipogenesis pathways in these organs. Amounts of vaccenic acids (i.e., 18:1(n-7) FA) in 12- and 16-week ob/ob mouse liver were significantly increased compared to their controls, indicating enhanced de novo synthesis of this acid through 16:1(n-7) FA in the liver starting at 12 weeks of age. Coincidentally, synthesis of triacylglycerol from monoacylglycerol in the liver was also increased in ob/ob mice starting at 12 weeks of age, as revealed by simulation of triacylglycerol synthesis. Moreover, levels of lipotoxic lipid classes were significantly higher in ob/ob mice than their age-matched controls, supporting the notion that elevated lipotoxic components are tightly associated with insulin resistance in ob/ob mice. Taken together, the current study revealed that lipogenesis and lipotoxicity in ob/ob mice likely contribute to insulin resistance and provides great insights into the underlying mechanisms of diabetes and obesity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Juvenile visceral steatosis (JVS) mice, which show systemic L-carnitine deficiency, may be an animal model of Reye's syndrome because of its phenotype of fat deposition and mitochondrial abnormalities in the liver. In this study, we compared the characteristics of the L-carnitine transport in isolated hepatocytes from wild-type and JVS mice. The uptake of L-carnitine by wild-type hepatocytes was saturable and the Eadie-Hofstee plot showed 2 distinct components. The apparent Michaelis constant (K(m)) and the maximum transport rate (V(max)) were 4.6 micromol/L and 59.5 pmol/15 min/10(6) cells, respectively, for the high-affinity component, and 404 micromol/L and 713 pmol/15 min/10(6) cells, respectively, for the low-affinity component. The high-affinity L-carnitine uptake occurred via an active carrier-mediated transport mechanism, which is characterized by Na(+)-, energy-, and pH-dependency. On the other hand, the high-affinity uptake was absent in JVS hepatocytes, and the values of K(m) and V(max) for the low-affinity uptake were 475 micromol/L and 557 pmol/15 min/10(6) cells, respectively. The hepatic carnitine transport properties in wild-type hepatocytes were similar to those of high-affinity mouse Octn2-transfected HEK293 cells. This study suggests that Octn2-type carnitine transporter is dysfunctional in hepatocytes of JVS mice.

A quantitative study of the effect of carnitine deficiency on expression of glycolytic and gluconeogenic enzymes was performed using juvenile visceral steatosis mice which are systemically deficient in carnitine. The amounts of glucokinase and L-type pyruvate kinase mRNA were reduced in homozygotes, compared to heterozygotes and normal controls at 2 and 8 weeks. Liver-type phosphofructokinase, however, did not differ significantly. The abundance of fructose 1,6-bisphosphatase mRNA was unchanged at 2 and 8 weeks. The level of phosphoenolpyruvate carboxykinase mRNA was increased slightly at 2 weeks, but not at 8 weeks. A part of these changes could not be explained by the plasma glucose or insulin level. Carnitine administration restored the mRNA of these enzymes to normal levels. These results suggest that carnitine deficiency affects the expression of these liver enzymes.

We conducted a quantitative study of the effect of carnitine deficiency on the mRNA level of carnitine palmitoyltransferase II in the liver, muscle and heart of mice with juvenile visceral steatosis, a strain that is systematically deficient in carnitine. The amount of carnitine palmitoyltransferase II mRNA was increased in liver and muscle of homozygotes, as compared with heterozygotes and normal controls, at 2, 4, and 8 wk of age. The mRNA levels of this enzyme were normalized after carnitine administration. The mRNA level of carnitine palmitoyltransferase II in the heart was increased only at 8 wk, and was not affected by carnitine administration. These results suggest that carnitine displays some effect on the mRNA level of the carnitine palmitoyltransferase II gene in liver and muscle, probably through fatty acid metabolic change.

We evaluated the change in arterial ketone body ratio (AKBR), which is a parameter to indicate the liver cells, during gastrectomy, and effect of PGE1 on its change in the elderly patients, compared with the younger patients. Twenty patients studied were elderly (above 65 years) and twenty were younger (below 60 years). PGE1 was administered in 10 elderly and 10 younger patients, and the remainders did not receive PGE1. Decrease in AKBR during the resection of stomach and immediate increase in AKBR after the resection of stomach were observed in younger patients. On the other hand, prolonged decrease in AKBR after the resection of stomach was observed in elderly patients. Administration of PGE1 accelerated the restoration of AKBR after the resection of the stomach in elderly patients and caused an increase in AKBR during the resection of stomach in younger patients. These findings suggest that hepatic functional capacity in elderly patients is less than that in younger patients, and that administration of PGE1 has a protective effect on liver in both elderly and younger patients.

We evaluated the effect of prostaglandin E1 (PGE1) on arterial ketone body ratio (AKBR), which is a parameter to indicate the function of the liver cells, in the patients undergoing total or subtotal gastrectomy. Twenty patients were divided into two groups: continuous intravenous administration of PGE1 (0.02 micrograms.kg-1.min-1) was started from 30 minutes after the beginning of the operation in 10 patients, and the remainders did not receive PGE1. AKBR levels at 30 minutes after the beginning of the operation (during the resection of stomach) were significantly lower than those after the resection of stomach in both groups. A significant increase in AKBR caused by the administration of PGE1 was observed during the resection of the stomach in PGE1 group. However, almost no change was observed in AKBR during the resection of the stomach in control group. These findings suggest that the administration of PGE1 has a protective effect on liver which is due mainly to the increase in hepatic blood flow during the resection of stomach.

Previous studies in our laboratories have revealed that juvenile visceral steatosis mice show suppressed transcription of urea cycle enzyme genes during development and are systemically deficient in carnitine. It has not yet been explained, however, how this carnitine deficiency relates to the abnormal gene expression. We investigated the effect of carnitine on abnormal gene expression, growth retardation, and fatty liver. Carnitine administration relieved the suppression of the developmental induction of two urea cycle enzymes examined, carbamoyl-phosphate synthetase and argininosuccinate synthase, and kept the activities of enzymes normal. However, carnitine did not reduce accumulated lipid in the liver to the normal level. These results suggest that carnitine deficiency plays an important role in the abnormal expression of urea cycle enzyme genes and that the abnormal expression of the genes is not directly caused by lipid accumulation in the liver.

Tissues were collected to survey the actual conditions of tetracycline antibiotics (TCs) residues in slaughtered animals that did not pass inspection at slaughterhouses in Aichi Prefecture, Japan, because of the presence of disease symptoms. Tissues were analyzed by liquid chromatography. Among 271 samples, 49 (18.1%) were positive for oxytetracycline (OTC), 5 (1.8%) for chlortetracycline (CTC), and 5 (1.8%) for doxycycline (DC), respectively. One sample (cattle kidney) was positive for both OTC and DC. However, tetracycline was not detected in any samples. Percentage frequencies of TCs residues were 29.1% (37/127) and 15.2% (22/144) for cattle and hogs, respectively. Kidney samples showed higher incidence of TCs residues and 1.5-7 times higher residual concentrations than liver and miscellaneous samples.

A carboxylesterase which shares common antigenicity with sex-influenced esterase (ES-SI) was found in both the male and the female liver of the rat but not in the following tissues: erythrocyte, heart, kidney, lung, spleen, small intestine, testis, thymus, and lymph node. Subcellular fractionation showed the esterase localizes in the microsome-rich fraction. The strain distribution of the presence or absence of the esterase in inbred rats was identical to that of ES-SI, although in adult males a considerable amount of the esterase exists, unlike ES-SI. The esterase had a higher isoelectric point than ES-SI but after neuraminidase treatment the difference disappeared, suggesting that the esterase has a sialic acid moiety. Because this esterase has different properties from those previously reported, it is proposed that it is designated liver-ES-SI. The common antigenicity and similar strain distribution between ES-SI and liver-ES-SI suggest that liver-ES-SI is a precursor molecule of ES-SI and therefore the two esterases are products of a single gene.

We analyzed carnitine profiles in C3H-H-2 degrees 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.

Arterial blood ketone body ratio (AKBR; acetoacetate/beta-hydroxybutyrate) is known as a parameter to indicate the function of the liver cells. We evaluated the effects of induced hypotension with prostaglandin E1 (PGE1) or trimetaphan (TMP) on AKBR in patients without liver disease undergoing mastectomy. Almost no change was observed in AKBR before, during and after hypotension with PGE1, but slight diminution was observed during hypotension with TMP. No hepatic dysfunction, however, developed in these patients postoperatively. These findings suggest that usual hypotension with TMP may provoke no postoperative hepatic dysfunction in patients without liver disease. For the patient who required either hypotension of long duration or hypotension with other factors affecting function of liver (surgical procedures, drugs and others), we prefer PGE1 to TMP as a hypotensive drug. We should also adopt PGE1 when cardiovascular control with hypotensive drug is necessary in patients with liver disease.

We determined the activities of urea cycle enzymes in the liver of C3H-H-2 degree-jsv mice. The activities of all urea cycle enzymes decreased in the latter period of lactation. The activities of carbamylphosphate synthetase and ornithine transcarbamylase in some affected mice were undetectable. On the other hand, the activities of enzymes other than urea cycle enzymes were normal. We consider that the decrease in the urea cycle enzymes is caused by an abnormality in the mechanism of gene expression.

The clinical, biochemical and histopathological findings of an infantile disease occurring in the C3H-H-2 degree strain of mice, which has similarities with Reye's syndrome in children, is described.

Two types of liver-specific F antigen in mice were distinguished by an immunoblotting technique after IEF of liver extracts. The IEF banding patterns consist of several bands whose pI vary from 7.57 to 8.15. One type of antigen (designated F2 antigen) showed a pattern that lacked some basic bands which are present in the pattern of the other type of antigen (designated F1 antigen). The latter type was found in AKR, CBA, C3H, DBA/2, and SM strains, while the former type was found in A, C57BL, and many other strains. Breeding experiments indicated that this variation is controlled by a single autosomal locus designated Laf (liver antigen F). Linkage analysis showed that the Laf locus is linked to the Pgm-1 locus on chromosome 5. The recombination frequency between these two loci is estimated to be 0.173 +/- 0.037. The distribution of F1 and F2 antigen types among inbred strains is concordant with that of type 1 and type 2 F antigens, which have been previously distinguished by their immunogenic differences, i.e., whether alloimmunization with the liver extracts from a given strain of mice can produce the antibody to F antigen in certain strains of mice. It is suggested, therefore, that the Laf locus may encode an allogeneic moiety of F antigen molecules.