We found that fatty liver is easily induced in a novel experimental animal, Suncus murinus (suncus) by withholding food. Hepatic triglyceride content increased linearly for up to 24 hours after fasting in these animals, while the glycogen content decreased. Although the glycogen contents returned to the level before fasting at 12 hours after refeeding, the triglyceride contents decreased gradually but did not reach to the level before fasting even at 24 hours after refeeding in suncus. Plasma lipids, glucose and insulin levels decreased by fasting and returned to the levels before fasting between 8 and 24 hours after refeeding. On the other hand, the plasma levels of free fatty acid and ketone bodies were elevated significantly by fasting and decreased rapidly by refeeding. These responses to fasting and refeeding except for the change in hepatic triglyceride are in common with other experimental animals, suggesting that there are no abnormalities not only in glucose metabolism but also in fatty acid metabolism.
The study of lipoproteins from this animal revealed that small amounts of lipoproteins with apolipoprotein (apo) E but without apoB were observed in the fraction of density less than 1.08g/ml. In order to learn whether apoB is synthesized by the liver or not, isolated suncus livers were perfused with an addition of [³⁵S] methionine. Small amounts of radioactivity were observed in apoE of VLDL, and fairly large amounts in apoE and A-I in the fraction of LDL+HDL, suggesting that VLDL was secreted with apoE but not with apoB from the liver. Northern blot analysis with use of rat apoB cDNA revealed a weak signal of hybridized rat apoB cDNA between 15Kb and 9Kb in the suncus liver and intestinal mucosa; this is almost the same size as rat apoB mRNA. This finding suggests the presence of apoB mRNA in the suncus.
In conclusion, apoB is not secreted from the suncus liver, owing to a defect in intracellular posttranscriptional processing or to ineffective transcription. This might be one of the reasons for fatty deposits in the suncus liver. Suncus may be a candidate for an animal model of abetalipoproteinemia as well as fatty liver due to a defect of apoB synthesis.

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It has been known that anion exchange resin and nicotinic acid effectively reduced plasma cholesterol and concomitantly decreased the events of coronary heart disease. This drug regimen was subsequently found to inhibit the progression of coronary atherosclerotic lesions.
Substantial reduction of total cholesterol or low denstty lipoprotein (LDL) cholesterol is primarily required to obtain the regressive alterations of coronary narrowings. However, in spite of the satisfactory reduction of LDL, some patients still develop the progression of the stenosis. The comparison of other variables of plasma lipids in the patients with or without progressive changes, indicates that the decrease in triglyceride and increase in high density lipoprotein (HDL)-cholesterol are necessary in order to maintain the non-progressive changes.

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Distributions of HDL particle size in coronary atherosclerosis defined by coronary angiography (CAG) were investigated. Subjects were 85 patients with coronary artery stenosis (CS+) positive (stenosis≥75%) and 64 with CS negative (stenosis<75%). Thirty-five of the CS(+) patients and 29 of the CS(-) patients had no histoty of diabetes mellitus, smoking or hyperlipidemia. In all of subjects, TC and TG levels were mesured by an autoanalyzer and apoprotein levels by the TIA method. HDL-C was obtained by the dextran sulfate-Ca precipitaion method, LDL-C was caculated by Friedewald's equation. Distributions of HDL subfractions were obtained by 4-30% PAGE. The absolute amounts of HDL subfractions were estimated as HDL-subfraction cholesterol concentrations by multipling plasma HDL-C concentration by percentage of HDL subclasses using PAGE.
Among all subjects, fasting plasma glucose levels and number of cigarettes smoked/daily were significantly higher in the CS(+) group. There were no significant differeces in TC, TG, LDL-C, apoA-II and apoB levels between CS(+) and CS(-) patients. CS(+) patients had significantly lower HDL-C and apoA-I levels than CS(-) patients both overall and in patients with no history of diabetes mellitus, smoking or hyperlipidemia. (p<0.05, p<0.01). Overall, there were no significant differences in percent distribution of HDL subfractions between CS(+) and CS(-) patients. In CS(-) patients, plasma concentrations of HDL2b-C, HDL2a-C, HDL3a-C and HDL3b-C were 13.1±11.3mg/dl, 14.4±7.5mg/dl, 13.9±5.4mg/dl and 3.6±2.5mg/dl, respectively, in CS(+) patients, these values were 7.8±6.9mg/dl, 13.4±7.1mg/dl, 12.1±5.4mg/dl and 3.1±2.2mg/dl. In patients negative for diabetes mellitus, smoking and hyperlipidemia, CS(+) patients had significantly lower percentage of HDL2b (p<0.01) and significantly higher HDL3a (p<0.05) than CS(-) patients. In CS(-) patients, plasma concentrations of HDL2b-C, HDL2a-C, HDL3a-C and HDL3b-C were 18.9±15.2mg/dl, 17.7±7.1mg/dl, 12.2±5.2mg/dl and 2.8±2.4mg/dl, respectively, in CS(+) patients, these values were 7.1±6.1mg/dl, 15.8±7.0mg/dl, 11.9±4.6mg/dl and 2.8±2.0mg/dl. Both in all patients and in patients negative for diabetes mellitus, smoking and hyperlipidemia, CS(+) patients scored significantly lower than CS(-) patients only in plasma HDL2b-C concentration (p<0.01). In all patients, coronary atherosclerosis score (CAS) by AHA classification had no correlation with any of the HDL subtraction concentrations.
However CAS correlated negatively with plasma HDL2b-C level in patients negative for diabetes mellitus, smoking and hyperlipidemia (r=-0.386, p<0.01).
We conclude that the plasma levels of large HDL particle (HDL2b) are low in subjects with coronary atherosclerosis.

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To clarify the differnces between the sexes in terms of ischemic heart disease, we examined the differential effects of visceral fat accumulation on lipid and glucose parameters, as well as the severity of coronary heart disease in 315 patients (172 males and 143 females) who had undergone coronary angiography. Total cholesterol, HDL-cholesterol, total amount of glucose during oral glucose tolerance tests, age, and smoking were independent coronary risk factors among males. For females, the independent coronary risk factor were the toal amount of glucose during oral glucose tolerance tests, the inverse of total amount of insulin during oral glucose tests, and total cholesterol. The amount of visceral fat was independently associated with the total amount of glucose, the insulin concentration at 120 minutes during glucose tolerance tests, and triglyceride levels among males. Among females, the total amount of visceral fat was associated with the insulin concentration at 120 minutes during glucose tolerance tests, and the inverse of the HDL-cholesterol and apolipoprotein B levels. The amount of visceral fat was an independent factor for apolipoprotein B concentration among females, but not among males. The effect of the amount of visceral fat on the metabolic variables was greater than the ratio of visceral fat to subcutaneous fat, particularly in the non-obese group. The joint effect of visceral fat accumulation and hyperternsion on coronary artery stenosis was greater among females than among males. Regarding metabolic profiles in the hypertensive visceral fat accumulation group, plasma insulin, the total amount of insulin during oral glucose tests and triglyceride concentrations were elevated among males. On the other hand, among females, the fasting plasma concentration of glucose and the total amounts of glucose during oral glucose tolerance tests, triglycerides, and apolipoprotein B were elevated, while the HDL-cholesterol concentration decreased. However, the basal insulin concentration and the total amounts of insulin during oral glucose tolerance tests were unchanged.
We concluded that visceral fat accumulation affected lipid and glucose metabolism among males and females, differently, and that it was a significant determinant of differences between the sexes for coronary heart disease.

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We investigated the in vitro effects of probucol on the oxidation of isolated low density lipoprotein (LDL) and of plasma by cupric ions. We also studied changes in the concentrations of lipid peroxides and antioxidants in circulating blood following the oral administration of probucol.
(1) LDLs were dose-dependently oxidized in vitro by cupric ions. The oxidation of LDL by cupric ions was markedly enhanced in the presence of monocytes. Probucol markedly inhibited the oxidation of LDL. The antioxidant effects of probucol were more marked in the presence of cupric ions. On the other hand, plasma was only very slightly, if at all, oxidized by cupric ions in vitro, and the antioxidant effects of probucol were not clear. It was suggested that the antioxidants in plasma (particularly, vitamin C) and/or plasma protein protected plasma lipids from oxidation by cupric ions.
(2) After 500mg probucol were administered daily for two weeks, the thiobarbituric acid reactive substances of plasma decreased significantly, although the hydroperoxide of the plasma lipids remained unchanged.
(3) An increase in the plasma ubiquinol-10/ubiquinone-10 ratio was observed after the oral administration of probucol, suggesting some protective effects of probucol on ubiquinol-10 which is regarded as a natural antioxidant in vitro.

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The effects of single and combined pravastatin and probucol therapy on serum lipids and lipoproteins were studied in patients with serum hypercholesterolemia with a total cholesterol level higher than 220mg/dl. The patients were nonselectively divided into 2 groups, Group A (36 patients, 59.2±9.7 y. o.) and Group B (31 patients, 62.8±9.2 y. o.). The two groups were statistically identical in terms of age, sex, serum lipid levels, body weight and complicated diseases. After 4 weeks of observation, Group A received single pravastatin therapy (10mg/day, bid.) while Group B received single probucol therapy (500mg/day, b. i. d.) for 12 weeks. Then both groups received a combined therapy of 10mg/day pravastain and 500mg/day probucol for an additional 12 weeks.
A significant decrease in total cholesterol (TC) was observed after 8 to 10 weeks in the subjects receiving 10mg of pravastatin (Group A, from 269±35mg/dl) to 219±34mg/dl (-20.2%)), and in the subjects receiving 500mg probucol (Group B, from 276±33mg/dl to 221±34mg/dl (-19.1%)). Moreover the decrease in both groups was statistically identical. Following the combined therapy for an additional 8 to 12 weeks, TC was further decreased to 193±31mg/dl (-29.6%) in Group A and to 187±28mg/dl (-31.5%) in Group B. Although the changes in triglyceride (TG) were not significant, the average TG level gradually decreased in both groups. The decreases in LDL-C by single pravastatin (-23.6%), by single probucol (-20.0%), and by combined therapy (-30.4% in Group A and -35.8% in Group B) were also statistically significant and identical in both groups. The decreases in TC and LDL-C were not influenced by the subjects' complicated diseases. Although HDL was significantly increased by pravastatin (+11.6%) and decreased by probucol, it was slightly reduced in both groups by the combined therapy. The changes in HDL-C were due to changes in HDL₂-C, as HDL₃-C remained unchanged. The atherogenic index (LDL-C/HDL-C) was significantly decreased by pravastatin, slightly increased by probucol, and decreased by the combined therapy. Changes in apoA-1 were proportional to changes in HDL-C and HDL₂-C, apoB to LDL-C and apoC-II and C-III to TG. Except for a slight increase in CPK, r-GTP, LDH and al-phos in several cases, no evident side effects were observed during either single or combined therapy.
These results indicate that single therapy either by 10mg pravastatin or by 500mg probucol is equally and moderately effective in reducing TC, LDL-C and the atherogenic index, and that combining the two improved these effects without producing evident side effects.

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