A 41-year-old female patient with muscle dystrophy, hepatosplenomegaly and tendinous xanthoma showed mild hypertriglyceridemia. The lipoprotein profile in blood showed increases in triglycerides in VLDL and LDL, and a marked decrease of cholesterol in HDL. Chylomicronemia was found, but was not severe. Both lipoprotein lipase and hepatic triglyceride lipase activities were reduced to a level that was only a few percent of the control. Immunoblotting study revealed that the IgG autoantibody in her serum was apparently reactable with hepatic triglyceride lipase and weakly with lipoprotein lipase. Hypertriglyceridemia in this patient is suggested to be due to the autoantibody to these lipases.

One hundred twenty-five patients with chronic hepatitis C were treated with natural IFNα or recombinant IFNα-2a, daily doses of 3 MU or 9MU, respectively. IFNs were given 6 times a week for the first 2 weeks followed by thrice weekly administration for 12 weeks or more. ANA, TMA, AMA and anti-DNA antibody newly developed in 8, 1, 2 and 1 patient, respectively. Furthermore, we encountered some cases in which underlying autoimmune disorders were throught to be exacerbated by IFNs. It is important to pay sufficient attention to the development of autoimmune diseases in IFN therapy for chronic hepatitis C.

BACKGROUND:Prostaglandin (PG) is reported to be involved in hepatic regeneration. However, little is known about the detailed relation in PG-induced stimulation of the proliferation. The present study was attempted to elucidate the relation. METHODS:The serial change of PGE2 level released from the regenerating rat liver and the effect of PGE2 on the proliferation of rat hepatocytes were studied, with special reference to PGE2 binding and cyclic AMP (cAMP). RESULTS:The PGE2 level increased 3 hours and 10 hours after partial hepatectomy. Timings of these increases seemed to coincide with those of the first and second increase of cAMP in the liver before the initiation of DNA synthesis. DNA synthesis of hepatocytes in primary culture between 24 and 36 hours, 36 and 48 hours, and 48 and 60 hours of culture were significantly enhanced by addition of PGE2 between 4 and 24 hours of culture at concentrations of 2 nmol/L to 1 mumol/L, 2 nmol/L to 200 nmol/L, and 5 mumol/L to 10 mumol/L, and 2 nmol/L and 10 mumol/L, respectively. Enhancement of DNA synthesis with PGE2 at concentrations less than 1 mumol/L seemed to be associated with the high-affinity binding and that at high concentrations with the low-affinity binding. Intracellular cAMP level in the hepatocytes increased during culture, and its increase was enhanced by PGE2 addition. CONCLUSIONS:It is suggested that PGE2 production in the liver increases biphasically during hepatic regeneration and that PGE2 enhances the proliferation of hepatocytes by a specific receptor-mediated process, which is largely associated with cAMP-dependent process.

Specific bindings of [3H]prostaglandin E1 ([3H]PGE1), 125I-glucagon and [3H]norepinephrine to D-galactosamine (GalN)-treated rat hepatocytes in primary culture were investigated. After a two hour-treatment with GalN (1 and 10mg/ml), hepatocytes showed an enhanced specific binding to [3H]PGE1, whereas 125I-glucagon binding was little affected and [3H]norepinephrine binding was strongly diminished. Scatchard plot analysis indicated an increase of binding sites of [3H]PGE1. This unusual manner of [3H]PGE1 binding is suggested to indicate a special property of PGE1 receptor and may be associated with the cytoprotective effect of prostaglandins.

Lipoprotein metabolism was studied by analyses of apolipoproteins, cholesterol content in lipoproteins and electrophoresis. The findings obtained suggested that the apolipoprotein levels such as A1 and B are related with particle number of lipoproteins such as HDL and LDL, while cholesterol content in lipoproteins is affected by qualitative change in particles as well. In patients with diabetes mellitus (NIDDM), LDL cholesterol correlated with HbA1c, and cholesterol and apolipoprotein B in the beta-area on electrophoresis showed accelerated mobilities, which were mimicked by in vitro glycation of LDL. In coronary heart diseases, elevation of apolipoprotein B and a low level of HDL cholesterol were general findings. The B/A1 ratio could be a sensitive indicator for these diseases. Hyper HDL cholesterolemias, excluding the patients with prostatic cancer who had undergone estrogen-treatment, showed elevated levels of apolipoprotein E in alpha 2-area on electrophoresis. Heterogeneity in Hyper HDL cholesterolemia was implicated. Qualitative analysis of lipoproteins by our method is believed to be useful.

Hypercitrullinemia (adult type), believed to be one of the hereditary urea cycle disorders, is known to be complicated by hepatocellular carcinoma at a high incidence (approximately 14%). We investigated the relationship between this hypercitrullinemia and hepatocarcinogenesis. After the addition of citrulline, incorporation of tritiated thymidine into primary cultured hepatocytes of adult rat increased in a dose-dependent fashion in the range of 0.1 to 5 mmol/L. The citrulline-added group also showed significant increase in ornithine and polyamine contents in hepatocytes. The incidence of epithelial cell foci in the in vivo-in vitro tumor promotion analyzing system significantly rose in the group maintained with 5 mmol/L citrulline and in the group maintained with 1.5 mmol/L phenobarbital. These findings suggest the possibility that citrulline has a promotion effect on hepatocyte proliferation and that at high concentrations it plays the role of a hepatocarcinogenesis promoter.

HDL cholesterol (HDL-Ch)/apolipoprotein A-I (A-I) ratio was studied in fourteen healthy students, fifteen male habitual drinkers, five male patients with chronic hepatitis (CH) and seven controls. HDL-Ch/A-I ratio in male students, female students, male drinkers, CH and control were 0.36 +/- 0.029, 0.39 +/- 0.03, 0.41 +/- 0.065, 0.40 +/- 0.02, and 0.36 +/- 0.039, respectively. Elevation of HDL-Ch/A-I ratio in female students, male drinkers and CH were statistically significant compared with control, while there was no significant change in HDL-Ch or A-I in female students but the elevations of both in male drinkers or the reduction of A-I in CH. Positive correlations were found between HDL-Ch/A-I ratio and HDL2-Ch, and HDL2-Ch/HDL3-Ch ratio in students and CH. The elevation of HDL-Ch/A-I ratio in CH appeared to be related to the reduction of HDL3-Ch. It is suggested that HDL-Ch/A-I ratio could indicate HDL2-Ch/HDL3-Ch ratio and is useful parameter for analysis of HDL metabolism.

The effect of alcohol intake on the serum levels of high-density lipoprotein cholesterol (HDL-ch), apoprotein A-I (apo A-I), and apoprotein A-II (apo A-II) was investigated in 15 habitual alcohol drinkers without liver injury (group A), 17 with mild hepatic damage (group B), and five with advanced liver disease (group C). The serum level of HDL-ch was higher in group A than in 10 nondrinkers (P less than 0.01) but lower in group B (P less than 0.05) and markedly lower in group C (P less than 0.01). The level of apo A-I was also higher in group A (P less than 0.05), although the level of apo A-II was not. To elucidate the effect of alcohol on apo A-I production by hepatocytes, the synthesis of apo A-I and albumin by cultured rat liver cells in the presence of ethanol was also investigated. Ethanol enhanced the production of apo A-I but not that of albumin. The results suggest that serum HDL is elevated in habitual alcohol drinkers without liver injury and that the elevation of HDL in blood is mainly dependent on the increase of apo A-I synthesis in the liver.

We studied in this paper the behavior of immunosuppressive and fibroblast proliferation inhibitory factors in the acute, chronic damage and cirrhotic alteration of the liver.

Protein kinase C (PKC) activity in the soluble fraction of regenerating rat liver showed a biphasic decrease prior to the initiation of DNA synthesis. The first decrease was seen at 3-6 h after partial hepatectomy (PH). The second decrease occurred after 14 h and continued until 24 h, while DNA synthesis began 18-20 h and reached peak value 22 h after PH. It is suggested that the soluble PKC in regenerating rat liver is activated and bound to the plasma membrane prior to the initiation of DNA synthesis.