High lovastatin doses combined with hypercholesterolemic diet induce hepatic damage and are lethal to the CD-1 mouse.

The addition of 1% lovastatin (LVT) to hypercholesterolemic diets [1% cholesterol or 1% cholesterol plus 0.1% sodium deoxycholate (HD)] induced hepatic damage and was lethal to CD-1 mice in the first days of treatment; the females were more resistant than males. LVT or HD administered alone was harmless to male or female mice. After a 3-day treatment all groups that received LVT (1%, 0.1% or 0.05%) plus HD showed a higher percentage of liver weight, with respect to whole body weight. Cholesterol serum levels increased in males with HD, but remained low in female mice. In the liver, total lipids and cholesterol levels increased in male mice with HD, but cholesterol remained unchanged in females. The addition of LVT to HD prevented the increase of serum and liver cholesterol levels in male mice. These results allow us to propose the CD-1 male-mouse as a model to evaluate the toxicity of LVT or other vastatins.     

Hypolipidemic effect of the edible mushroom Agaricus blazei in rats subjected to a hypercholesterolemic diet

The effects of Agaricus blazei intake on the lipid profile of animals fed a hypercholesterolemic diet were evaluated. Thirty-two female Fisher rats were divided into four groups and given the standard AIN-93 M diet (C), this diet?+?1 % A. blazei (CAb), a hypercholesterolemic diet with 25 % soybean oil and 1 % cholesterol (H) or this diet?+?1 % A. blazei (HAb) for 6 weeks. Food intake, weight gain, liver and serum lipid profiles, activity of aminotransferases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)], and creatinine and urea levels as well as abdominal fat weight were measured. Histological analysis of kidney and liver tissue was also performed. The HAb group had a higher food intake, but a lower weight gain as compared to group H. This resulted in a significant decrease in abdominal fat weight, to values close to those of groups C and CAb. Supplementing the hypercholesterolemic diet with A. blazei promoted a significant reduction in total and non-HDL cholesterol, as well as in the atherogenic index, as compared to group H, and this effect was more pronounced in the serum. There was no hepatotoxic effect caused by the supplementation of the diets with the mushroom. We conclude that in our experimental model and in the concentration used, A. blazei was effective in improving the lipid profile of the animals.     

Arthrospira maxima prevents the acute fatty liver induced by the administration of simvastatin,ethanol and a hypercholesterolemic diet to mice

An evident fatty liver, corroborated morphologically and chemically, was produced in CD-1 mice after five daily doses of simvastatin 75 mg/Kg body weight, a hypercholesterolemic diet and 20 percent ethanol in the drinking water. After treating the animals, they presented serum triacylglycerols levels five times higher than the control mice, total lipids, cholesterol and triacylglycerols in the liver were 2, 2 and 1.5 times higher, respectively, than in control animals. When Arthrospira maxima was given with diet two weeks prior the onset of fatty liver induction, there was a decrement of liver total lipids (40%), liver triacylglycerols (50%) and serum triacylglycerols (50%) compared to the animals with the same treatment but without Arthrospira maxima. In addition to the mentioned protective effect, the administration of this algae, produced a significant increase (45%) in serum high density lipoproteins. The mechanism for this protective effect was not established in these experiments.     

Serum Cholesterol-Decreasing Effect of Heat-Moisture-Treated High-Amylose Cornstarch in Cholesterol-Loaded Rats

Rats were fed on a diet containing cholesterol (Chol) at a level corresponding to the standard Chol intake in humans, and the influence of heat-moisture-treated high-amylose cornstarch (HHA) on their serum Chol level was investigated. HHA decreased the serum level of Chol in rats fed on the diet containing 0.1% Chol, which corresponds to a Chol intake in humans of 800 mg/d, although the liver levels of Chol increased in these rats. HHA did not influence the fecal excretion of Chol/bile acids. It is possible that the decrease in serum Chol level in the rats fed on the high-Chol diet can be attributed to the promotion of Chol uptake in the liver.     

Serum cholesterol-decreasing effect of heat-moisture-treated high-amylose cornstarch in cholesterol-loaded rats

Rats were fed on a diet containing cholesterol (Chol) at a level corresponding to the standard Chol intake in humans, and the influence of heat-moisture-treated high-amylose cornstarch (HHA) on their serum Chol level was investigated. HHA decreased the serum level of Chol in rats fed on the diet containing 0.1% Chol, which corresponds to a Chol intake in humans of 800 mg/d, although the liver levels of Chol increased in these rats. HHA did not influence the fecal excretion of Chol/bile acids. It is possible that the decrease in serum Chol level in the rats fed on the high-Chol diet can be attributed to the promotion of Chol uptake in the liver.     

Diet-dependent obesity and hypercholesterolemia in the New Zealand obese mouse: identification of a quantitative trait locus for elevated serum cholesterol on the distal mouse chromosome 5

AIMS: New Zealand obese (NZO) mice exhibit a polygenic syndrome of obesity, insulin resistance, and hypercholesterolemia that resembles the human metabolic syndrome. This study was performed in order to locate genes responsible for elevated serum cholesterol and to compare their effects under a standard and high fat diet.METHODS: A backcross population of NZO with SJL mice (NZO x F1(SJL x NZO)) was generated. Mice were raised on a normal or high fat diet and were monitored for 22 weeks (body weight, serum cholesterol, and blood glucose). A genome-wide scan was performed by genotyping of approximately 200 polymorphic microsatellite markers by PCR and linkage analysis was performed with the MAPMAKER program.RESULTS: In the genome-wide scan, a single susceptibility locus for hypercholesterolemia (Chol1/NZO, maximum LOD score 14.5 in a combined population of 523 backcross mice) was identified on chromosome 5. Cholesterol levels were significantly elevated in both male and female homozygous carriers of the Chol1/NZO allele. The locus maps 40cM distal of the previously described obesity locus Nob1 in the vicinity of the marker D5Mit244 and in the vicinity of hypercholesterolemia QTL previously identified in the NZB, CAST, and C57BL/6J strains. Chol1/NZO was not associated with elevated body weight, serum insulin, or hyperglycemia. The high fat diet significantly increased serum cholesterol levels, but the fat content of the diet did not alter the absolute effect of Chol1/NZO.Conclusions: Chol1/NZO is a major susceptibility locus on the distal mouse chromosome 5, which produces gender-independent hypercholesterolemia in NZO mice. The effect of Chol1/NZO was independent of the dietary fat content and was not associated with the other traits of the metabolic syndrome. Thus, it is suggested that the responsible gene might be involved in cholesterol metabolism.     

Lipid-lowering properties of 6-benzoyl-2(3H)-benzothiazolone and structurally related compounds

Fifteen compounds derived from the 2(3H)-benzothiazolone template with an acyl side-chain in position-6 were evaluated for their lipid-lowering action in mice. Among these compounds, 6-benzoyl-2(3H)-benzothiazolone was found to be the most potent one both in mice models receiving a hypercholesterolemic diet (for 15 days) or a standard diet (for 21 days). 6-Benzoyl-2(3H)-benzothiazolone compares favorably with fenofibrate, the standard drug, both in terms of HDL-C/Chol (High Density Lipoprotein-Cholesterol/Total Cholesterol) ratio and absence of liver hepatomegaly.     

The effects of Coptidis Rhizoma extract on a hypercholesterolemic animal model

The serum cholesterol (total, free, esterified, low density lipoprotein (LDL) and oxidized LDL) levels of rats fed a diet containing, by weight, 1% cholesterol and 0.5% cholic acid increased, as compared with those of rats fed a normal diet. The levels, especially of total cholesterol, LDL and oxidized LDL, were reduced significantly in a dose-dependent manner, in rats given Coptidis Rhizoma extract orally at doses of 50 and 100 mg/kg body wt./day for 30 days. These results indicate that Coptidis Rhizoma extract is effective in reducing the pathological damage caused by hypercholesterolemia, through lowering of serum cholesterol levels. In addition, Coptidis Rhizoma extract reduced the level of liver cholesterol, but it did not reduce that of fecal cholesterol, suggesting that the cholesterol level-lowering effect resulted from the reduction of cholesterol synthesis, not the enhancement of its excretion. Furthermore, the serum thiobarbituric acid-reactive substance level decreased after oral administration of Coptidis Rhizoma extract, indicating that Coptidis Rhizoma could prevent hypercholesterolemic disease through reducing lipid peroxidation. This study demonstrates that Coptidis Rhizoma may be a useful therapy for hypercholesterolemia through reducing oxidative stress and cholesterol levels.     

Lipid-lowering properties of 6-benzoyl-2(3H)-benzothiazolone and structurally related compounds

Fifteen compounds derived from the 2(3H)-benzothiazolone template with an acyl side-chain in position-6 were evaluated for their lipid-lowering action in mice. Among these compounds, 6-benzoyl-2(3H)-benzothiazolone was found to be the most potent one both in mice models receiving a hypercholesterolemic diet (for 15 days) or a standard diet (for 21 days). 6-Benzoyl-2(3H)-benzothiazolone compares favorably with fenofibrate, the standard drug, both in terms of HDL-C/Chol (High Density Lipoprotein-Cholesterol/Total Cholesterol) ratio and absence of liver hepatomegaly.     

Black and green tea improves lipid profile and lipid peroxidation parameters in Wistar rats fed a high-cholesterol diet

In the present study, the efficacy of black tea (BT) and green tea (GT) was studied in relation to serum and hepatic oxidative abnormalities in hypercholesterolemic rats. Hypercholesterolemia was induced in male Wistar rats (8 week old) by feeding them with a high-cholesterol diet (HCD) for 35 days. The experimental rats were given BT and GT as a supplement (7 g/L) via drinking water. Increased hepatic and serum lipid profile along with abnormalities in oxidative marker, with a concomitant increase in the body weight, food intake, and food efficiency, were seen in hypercholesterolemic rats. Following the supplementation of BT and GT to rats fed with HCD, significantly lower levels of serum and hepatic cholesterol, triglycerides, serum low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol levels were observed, when compared with hypercholesterolemic group. Further, significantly lower levels in the serum and hepatic lipid peroxidation, body weight gain, and food efficiency were observed in BT and GT group when compared with control and HCD fed group. However, no such significant changes were observed in the food intake upon supplementation with BT and GT. These results suggest that supplementation of BT and GT may protect against the serum and hepatic abnormalities in hypercholesterolemic rats.     

Effect of Diets Containing Sucrose vs. D‐tagatose in Hypercholesterolemic Mice

Effects of functional sweeteners on the development of the metabolic syndrome and atherosclerosis are unknown. The objective was to compare the effect of dietary carbohydrate in the form of sucrose (SUCR) to D‐tagatose (TAG; an isomer of fructose currently used as a low‐calorie sweetener) on body weight, blood cholesterol concentrations, hyperglycemia, and atherosclerosis in low‐density lipoprotein receptor deficient (LDLr^−/−) mice. LDLr^−/− male and female mice were fed either standard murine diet or a diet enriched with TAG or SUCR as carbohydrate sources for 16 weeks. TAG and SUCR diets contained equivalent amounts (g/kg) of protein, fat, and carbohydrate. We measured food intake, body weight, adipocyte diameter, serum cholesterol and lipoprotein concentrations, and aortic atherosclerosis. Macrophage immunostaining and collagen content were examined in aortic root lesions. CONTROL and TAG‐fed mice exhibited similar energy intake, body weights and blood glucose and insulin concentrations, but SUCR‐fed mice exhibited increased energy intake and became obese and hyperglycemic. Adipocyte diameter increased in female SUCR‐fed mice compared to TAG and CONTROL. Male and female SUCR‐fed mice had increased serum cholesterol and triglyceride concentrations compared to TAG and CONTROL. Atherosclerosis was increased in SUCR‐fed mice of both genders compared to TAG and CONTROL. Lesions from SUCR‐fed mice exhibited pronounced macrophage immunostaining and reductions in collagen content compared to TAG and CONTROL mice. These results demonstrate that in comparison to sucrose, equivalent substitution of TAG as dietary carbohydrate does not result in the same extent of obesity, hyperglycemia, hyperlipidemia, and atherosclerosis.     

Correlation of serum hepatitis C virus RNA titre with aminotransferases and liver histopathological findings in HCV-seropositive cases with end-stage chronic liver disease

The quantity of circulating hepatitis C virus (HCV) RNA, aminotransferases and the degree of liver cell injury in relation to HCV serotype have not been fully studied. In this work, we estimated the HCV RNA titre in serum and correlated the findings with levels of aminotransferases, gamma glutamyltransferase (GGT), and liver histopathological changes and with HCV serotype. HCV RNA was found in 22 out of 30 HCV-seropositive cases included in this study (73. 3%) and serotype 4 represented 90.9% (20/22). Levels of aminotransferases and GGT correlated with the levels of serum HCV RNA. Noticeably, GGT showed the highest positive correlation with the level of HCV RNA. Liver histopathological findings of 15 patients showed that eight had hepatocellular carcinoma and seven had cirrhosis. There was no significant difference between these two groups regarding levels of enzymes or serum HCV RNA titre.     

Astaxanthin restricts weight gain,promotes insulin sensitivity and curtails fatty liver disease in mice fed a obesity-promoting diet

The study evaluated the effects of astaxanthin (ASX) in mice rendered obese by feeding an unbalanced diet. Adult male mice of body weight 25–35 g were fed either normal chow or a high fat-high fructose diet (HFFD). Fifteen days later, mice in each group were divided in to two and treated with either ASX (6 mg/kg b.w.) in olive oil or olive oil alone. The mice were killed at the end of 60 days. Insulin sensitivity, markers of liver injury, inflammation and nitro-oxidative stress, antioxidants and cytochrome P 4502E1 (CYP2E1) activity were assayed. Liver structural integrity was also assessed by histology with hemotoxylin and eosin and Masson's trichrome stains. HFFD-fed mice registered significant increase in body weight and liver weight and displayed hyperglycemia, hyperinsulinemia and insulin resistance and elevated plasma aminotransferases. Lipid deposition, oxidative damage, defective antioxidant system and upregulated transforming growth factor-β (TGF-β1) expression were observed in HFFD-fed mice. ASX supplementation promoted insulin sensitivity and prevented liver injury by decreasing CYP2E1, myeloperoxidase, and nitro-oxidative stress and by improving the antioxidant status in them. Lipid deposition and increased TGF-β1 expression induced by HFFD were also abolished by ASX. This study provides new data showing the beneficial effects of ASX in obese mice.     

不同运动方式对肥胖大鼠肝脏脂质沉积及FGF21分泌的影响*

目的: 研究持续性运动训练(CT)与高强度间歇运动训练(HIIT)对正常和肥胖大鼠血清和肝脏FGF21蛋白含量及肝脏脂肪代谢的影响。方法: 雄性SD大鼠随机分为两组:普通饲料及45%高脂饲料喂养,8周后以普通饲料喂养,大鼠体重增加20%为肥胖造模成功标准。将正常大鼠随机分为正常安静组(LC)、正常高强度间歇运动训练组(LHI)、正常持续性运动训练组(LCT),肥胖大鼠随机分为肥胖安静组(OC)、肥胖高强度间歇运动训练组(OHI)及肥胖持续性运动训练组(OCT),每组10只,运动干预组大鼠进行8周不同方式负重游泳运动训练干预,末次运动干预间隔24 h后取血液检测血清炎症因子、FGF21水平,取肝脏组织检测脂质含量、脂代谢酶含量及FGF21表达水平。结果: 与LC组比较,OC组大鼠体重、血清炎症因子、肝脏甘油三酯(TG)含量显著增高(P＜0.05),LHI组肝脏TG含量显著降低,LCT组肝脏FGF21表达水平显著增高(P＜0.05)。与OC组比较,OHI组大鼠肝脏TG含量显著降低(P＜0.05),线粒体CPT-1β、β-HAD酶含量显著升高(P＜0.05),OCT组大鼠肝脏LPL、FAT/CD36酶含量显著增高,血清、肝脏FGF21水平均显著上升(P＜0.05)。结论: 两种运动方式均能降低正常、肥胖大鼠体重及肥胖大鼠肝脏脂质沉积现象,其中HIIT上调线粒体脂肪氧化水平,显著降低正常、肥胖大鼠肝脏TG含量,而CT通过提高正常、肥胖大鼠肝脏FGF21蛋白表达及血清FGF21水平,促进肝脏摄取脂肪酸,对缓解肥胖大鼠肝脏脂质沉积效果有限。     

Effect of Cheonggukjang supplementation upon hepatic acyl-CoA synthase, carnitine palmitoyltransferase I, acyl-CoA oxidase and uncoupling protein 2 mRNA levels in C57BL/6J mice fed with high fat diet

This study investigated the effect of Cheonggukjang on mRNA levels of hepatic acyl-CoA synthase (ACS), carnitine palmitoyltransferase I (CPT-I), acyl-CoA oxidase (ACO) and uncoupling protein 2 (UCP2), and on serum lipid profiles in C57BL/6J mice. Thirty male C57BL/6J mice were divided into three groups; normal diet (ND), high fat diet (HD) and high fat diet with 40% Cheonggukjang (HDC). Energy intake was significantly higher in the HDC group than in the ND and HD groups. The HDC group normalized in weight gain, epididymal and back fat (g/100 g) accumulation which are increased by high fat diet. Serum concentrations of triglyceride and total cholesterol in the HDC were significantly lower than those in the HD group. These results were confirmed by hepatic mRNA expression of enzymes and protein (ACS, CPT-1, ACO, UCP2) which is related with lipid metabolism by RT-PCR. Hepatic CPT-I, ACO and UCP2 mRNA expression was increased by Cheonggukjang supplementation. We demonstrated that Cheonggukjang supplement leads to increased mRNA expressions of enzymes and protein involved in fatty acid oxidation in liver, reduced accumulation of body fat and improvement of serum lipids in high fat diet fed mice.     

Role of dietary lysine, methionine, and arginine in the regulation of hypercholesterolemia in rabbits

These experiments were conducted to see whether the hypercholesterolemia produced by a diet enriched in lysine (Lys) and methionine (Met) can be reproduced by feeding these amino acids separately, and whether dietary arginine (Arg) counteracts their hypercholesterolemic effects. Another aim was to investigate the mechanisms involved in modulations of serum cholesterol levels by these amino acids. The results of this study, which were in agreement with the results of earlier experiments in our laboratory, showed that feeding a low-fat, cholesterol-free, semipurified amino acid diet enriched with Lys + Met to rabbits caused a marked increase in serum total and low density lipoprotein cholesterol and apolipoprotein B levels, whereas a similar diet enriched in essential ketogenic amino acids (EketoAA) resulted in a more moderate increase in these parameters. Supplementing the diet with either Lys or Met alone was also less effective in inducing hypercholesterolemia than increasing levels of both amino acids. Dietary Arg partially counteracted the hypercholesterolemic effect of Lys + Met but not that of the EketoAA or of Lys and Met fed separately. The growth performance of rabbits fed the Lys + Met diet was inferior to that of those fed the other diets. Liver total phospholipid levels and the ratio of phosphatidylcholine to phosphatidylethanolamine were higher in rabbits fed the Lys + Met-enriched diet than in those animals fed a diet in which Arg was supplemented. In conclusion, our results indicate that high levels of both Lys and Met are needed to cause a maximum elevation of serum cholesterol and that the moderately antihypercholesterolemic effect of Arg is seen only when both amino acids are supplemented. They also suggest that these essential amino acids may affect cholesterol metabolism partly through alteration of liver phospholipids.     

Effects of increased dietary cholesterol with carbohydrate restriction on hepatic lipid metabolism in Guinea pigs

Excessive lipid accumulation within hepatocytes, or hepatic steatosis, is the pathognominic feature of nonalcoholic fatty liver disease (NAFLD), a disease associated with insulin resistance and obesity. Low-carbohydrate diets (LCD) improve these conditions and were implemented in this study to potentially attenuate hepatic steatosis in hypercholesterolemic guinea pigs. Male guinea pigs (n = 10 per group) were randomly assigned to consume high cholesterol (0.25 g/100 g) in either a LCD or a high-carbohydrate diet (HCD) for 12 wk. As compared with HCD, plasma LDL cholesterol was lower and plasma triglycerides were higher in animals fed the LCD diet, with no differences in plasma free fatty acids or glucose. The most prominent finding was a 40% increase in liver weight in guinea pigs fed the LCD diet despite no differences in hepatic cholesterol or triglycerides between the LCD and the HCD groups. Regardless of diet, all livers had severe hepatic steatosis on histologic examination. Regression analysis suggested that liver weight was independent of body weight and liver mass was independent of hepatic lipid content. LCD livers had more proliferating hepatocytes than did HCD livers, suggesting that in the context of cholesterol-induced hepatic steatosis, dietary carbohydrate restriction enhances liver cell proliferation.     

过表达apoA—I对小鼠非酒精性脂肪性肝炎作用的研究

目的研究非酒精性脂肪性肝炎（NASH）,脂肪酸（FFA）及载脂蛋白A1（apoA-I）三者之间的作用及其对预防治疗。NASH的意义。方法通过胆碱一蛋氨酸缺乏（MCD）饲料喂养的小鼠NASH模型,注射含有人apoA-I基因的腺病毒载体或对照腺病毒载体一周后,检测小鼠肝脏指数,血清谷丙转氨酶、谷草转氨酶水平,对肝脏切片进行油红O染色,检测血清和肝组织中甘油三酯（TG）,FFA及胆固醇（Ch01）的含量。结果与对照组相比,过量表达apoA—I的小鼠肝脏病变减轻,脂质堆积减少,血清谷丙转氨酶、谷草转氨酶水平有所下降,肝组织中TG,FFA及Chol含量明显降低,相应的其血清TG,Chol水平升高。结论过量表达apoA-I可通过减少小鼠肝脏中过量脂质的堆积而对NASH起到缓解作用。     

Subcutaneous lipectomy causes a metabolic syndrome in hamsters

The insulin resistance syndrome X is related to excess intra-abdominal adipose tissue. With lipectomy of >50% of subcutaneous adipose tissue (SQAT) in nonhibernating, adult female Syrian hamsters on high-fat (HF; 50 calorie%) diet and measurements of oral glucose tolerance, oral [(14)C]oleic acid disposal, serum triglycerides, serum leptin, liver fat, perirenal (PR) adipose tissue cellularity, and body composition, we studied the role of SQAT. Sham-operated (S) animals on HF or low-fat (LF; 12.5 calorie%) diets served as controls. After 3 mo there was no visible regrowth of SQAT but HF diet led to similar levels of body weight and body fat in lipectomized and sham-operated animals. Lipectomized (L) animals had more intra-abdominal fat as a percentage of total body fat, higher insulinemic index, a strong trend toward increased liver fat content, and markedly elevated serum triglycerides compared with S-HF and S-LF. Liver and PR adipose tissue uptake of fatty acid were similar in L-HF and S-HF but reduced vs. S-LF, and were inversely correlated with liver fat content and insulin sums during the oral glucose tolerance test. In summary, lipectomy of SQAT led to compensatory fat accumulation implying regulation of total body fat mass. In conjunction with HF diet these lipectomized hamsters developed a metabolic syndrome with significant hypertriglyceridemia, relative increase in intra-abdominal fat, and insulin resistance. We propose that SQAT, via disposal and storage of excess ingested energy, acts as a metabolic sink and protects against the metabolic syndrome of obesity.     

Liver copper content of rats hypo- or hyperresponsive to dietary cholesterol

The question addressed is whether cholesterol intake reduces the hepatic copper content in rats. For this purpose we have compared the hepatic copper content of two selected rat inbred strains after feeding the animals a control or a high fat, high cholesterol diet. One strain was dietary cholesterol resistant (SHR/OlaIpcv), whereas the other strain was susceptible to dietary cholesterol (BN-Lx/Cub). Dietary cholesterol-susceptible rats have a lower baseline hepatic copper content when compared with their resistant counterparts. The consumption of a hypercholesterolemic diet decreased the liver copper concentration (expressed in microg/g dry weight) to about the same extent in both strains. However, dietary cholesterol did not reduce the absolute (expressed as microg/whole liver) and relative (expressed as microg/whole liver/100 g body weight) copper store of rats. The decrease of liver copper concentration after the high fat, high cholesterol diet is probably not caused by a decrease in whole hepatic copper content, but rather due to dietary-induced hepatomegaly.