-Hyperhomocysteinemia is an independent risk factor for cardiovascular disorders. Elevated plasma homocysteine (Hcy) concentration is associated with other cardiovascular risk factors. We previously reported that Hcy stimulated cholesterol biosynthesis in HepG2 cells. In the present study, we investigated the underlying mechanisms of Hcy-induced hepatic cholesterol biosynthesis in an animal model. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a highmethionine diet for 4 wk. The mRNA expression and the enzyme activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase were significantly increased in livers of hyperhomocysteinemic rats. There were marked hepatic lipid accumulation and an elevation of plasma cholesterol concentration in hyperhomocysteinemic rats. Three transcription factors, namely, sterol regulatory element-binding protein-2 (SREBP-2), cAMP response element-binding protein (CREB), and nuclear factor Y (NF-Y) were activated in livers of hyperhomocysteinemic rats. Upon Hcy treatment of hepatocytes, there was a significant increase in HMG-CoA reductase mRNA expression in these cells. The activation of SREBP-2, CREB, and NF-Y preceded the increase in HMG-CoA reductase expression in Hcy-treated cells. Pretreatment of hepatocytes with inhibitors for transcription factors not only blocked the activation of SREBP-2, CREB, and NF-Y but also attenuated Hcy-induced HMG-CoA reductase mRNA expression. These results suggested that hyperhomocysteinemia-induced activation of SREBP-2, CREB, and NF-Y was responsible for increased cholesterol biosynthesis by transcriptionally regulating HMG-CoA reductase expression in the liver leading to hepatic lipid accumulation and subsequently hypercholesterolemia. In conclusion, the stimulatory effect of Hcy on hepatic cholesterol biosynthesis may represent an important mechanism for hepatic lipid accumulation and cardiovascular disorder associated with hyperhomocysteinemia.homocysteine; 3-hydroxy-3-methylglutaryl coenzyme A reductase; cAMP response element-binding protein; sterol regulatory elementbinding protein-2; nuclear factor Y HYPERHOMOCYSTEINEMIA, an elevation of blood homocysteine (Hcy) concentration, is considered an independent risk factor for cardiovascular and cerebrovascular disorders (7,37,48). The mechanisms responsible for hyperhomocysteinemia-associated cardiovascular disorders are still under investigation.

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Atherosclerosis is the leading cause of death in North America and within the next two decades will be the leading cause worldwide. Atherosclerosis is characterized by vascular obstruction from the deposits of plaque, resulting in reduced blood flow. Plaque rupture and the consequent thrombosis may lead to sudden blockage of the arteries and cause heart attack. High serum lipid levels, especially the elevated level of low-density lipoprotein (LDL), have been shown to be strongly related to the development of atherosclerosis. It is generally accepted that atherosclerotic lesions are initiated via an enhancement of LDL uptake by monocytes and macrophages. In the liver, uptake of plasma LDL is mediated via specific LDL receptors, but a scavenger receptor system is employed by macrophages. Plasma LDL must be modified prior to uptake by macrophages. Analysis of the lipid content in the oxidatively modified LDL from hyper lipidemic patients revealed that the level of lysophosphatidylcholine was greatly elevated, and the high level of the lysolipid was shown to impair the endothelium-dependent relaxation of the blood vessels. In a separate study, we showed that a high level of homocysteine caused the increase in cholesterol production and apolipoprotein B-100 secretion in hepatic cells. Statins have been used effectively to control the production of cholesterol in the liver, and recently, ezetimibe has been shown to supplement the efficacy of statins by inhibiting cholesterol absorption. The factor of elevated levels of triglyceride-rich lipoproteins in association with depressed high-density lipoproteins, usually in the context of insulin resistance, is an important contributor to atherosclerosis and can be effectively treated with fibric acid derivatives. In hyperhomocysteinemia, folic acid supplements may have a role in the control of cholesterol by reducing the plasma homocysteine level.

Hyperlipidemia is a known risk factor for fatty infiltration of the liver, a condition that can progress to cirrhosis and liver failure. The objectives of this study were to document the prevalence of fatty infiltration in the livers of hyperlipidemic patients and to identify the predictor variables associated with this condition. Over an 18-month recruitment period, clinical, biochemical, and radiologic assessments were performed in a cross-sectional manner in 95 adult patients referred to an urban hospital-based lipid clinic for evaluation and management of hyperlipidemia. The mean (+/-SD) age of the patients was 55 +/- 13 years. Forty-eight (51%) were male. Fifty-two patients (55%) had hypercholesterolemia, 25 (26%) severe hypertriglyceridemia, 14 (15%) mixed hyperlipidemia, and 4 (4%) moderate hypertriglyceridemia. Obesity and diabetes were present in 36 (38%) and 12 (12%) of cases, respectively. A total of 61 (64%) patients had elevated liver enzyme tests. The most common enzyme abnormalities were an elevated serum ALT in 45 (47%) and GGT in 43 (45%) of patients. Ultrasound findings revealed diffuse fatty liver in 47 patients (50%), of which 21 cases (22%) were mild, 18 (19%) moderate, and 8 (9%) severe. The majority of patients with hypercholesterolemia [35/52 (67%)] had normal ultrasounds, whereas severe hypertriglyceridemia and mixed hyperlipidemia were frequently associated with radiologic evidence of fatty liver (odds ratios 5.9 and 5.1 respectively, P < 0.01). Independent predictors of fatty liver were; AST (P = 0.001), hyperglycemia (P = 0.02), and age (P = 0.04). In a model incorporating known risk factors for fatty liver, diabetes was the only risk factor other than hypertriglyceridemia that was significantly associated with fatty infiltration. No such effect was seen with age, gender, obesity, or alcohol consumption. In conclusions, the results of this study indicate that ultrasonographic evidence of fatty infiltration of the liver is evident in approximately 50% of patients with hyperlipidemia. Hypertriglyceridemia is the lipid profile most often associated with this condition. Serum AST values, hyperglycemia, and age independently predict the presence of fatty infiltration, while hypertriglyceridemia and diabetes are the only risk factors that significantly increase the risk of fatty infiltration in hyperlipidemic patients.

The long-term prognosis of first-degree heart block in the absence of organic heart disease has not been clearly defined. We addressed this question in a 30-year longitudinal study of 3983 healthy men. We identified 52 cases that were present on entry into the study and 124 incident cases during follow-up. The incidence rose steadily after age 40 and was 1.13 per 1000 person-years over the entire period. Two thirds of the cases had only moderate prolongation of the PR interval (0.22 to 0.23 second). We compared four age-matched controls with each case for histories of scarlet fever, rheumatic fever, diphtheria, smoking, blood pressure, and body-mass index. No significant differences (P greater than 0.05) were found. Likewise, mortality from all causes did not differ between cases and controls. Although somewhat higher rates of morbidity and mortality from ischemic heart disease were observed in the cases than in the controls, the differences were not significant. Progression to higher grades of heart block occurred in only two cases. In view of the prognostic findings and the rare occurrence of advanced degrees of heart block, we conclude that primary first-degree heart block with moderate PR prolongation is a benign condition. This conclusion may not apply, however, to persons with more marked prolongation of the PR interval, a very rare condition.

Sitosterolemia is a rare autosomal recessive disorder of lipoprotein metabolism characterized by xanthomas and increased plasma concentrations of plant sterols, such as sitosterol. Causative mutations occur in either the ABCG5 or ABCG8 gene, each of which encodes a sterol half-transporter expressed in the intestine. We report five Canadian subjects with nonsense mutations in these half-transporters: four related Caucasian subjects were homozygous for the ABCG8 S107X mutation, and one unrelated Japanese-Canadian subject was homozygous for a complex insertion/deletion (I/D) mutation in ABCG5 exon 3. A female subject with each mutation was symptomatic with coronary atherosclerosis: a 5-year-old ABCG8 S107X homozygote and a 75-year-old ABCG5 exon 3 I/D homozygote; these represent the extreme ends of the spectrum of vascular involvement in sitosterolemia. The largest reductions in plasma concentrations of sitosterol and LDL-cholesterol were seen with ezetimibe or bile acid sequestrant treatment, and less dramatic reductions were seen with statin drug treatment. These findings extend the range of clinical phenotypes in sitosterolemia caused by nonsense mutations in either ABCG5 or

Current evidence indicates that foods with added plant sterols or stanols can lower serum levels of low-density lipoprotein cholesterol. This review summarizes the recent findings and deliberations of 31 experts in the field who participated in a scientific meeting in Winnipeg, Canada, on the health effects of plant sterols and stanols. Participants discussed issues including, but not limited to, the health benefits of plant sterols and stanols beyond cholesterol lowering, the role of plant sterols and stanols as adjuncts to diet and drugs, and the challenges involved in measuring plant sterols and stanols in biological samples. Variations in interindividual responses to plant sterols and stanols, as well as the personalization of lipid-lowering therapies, were addressed. Finally, the clinical aspects and treatment of sitosterolemia were reviewed. Although plant sterols and stanols continue to offer an efficacious and convenient dietary approach to cholesterol management, long-term clinical trials investigating the endpoints of cardiovascular disease are still lacking.

A 5-year-old girl with a recent history of recurrent abdominal pain presented with acute respiratory distress that rapidly became asystolic. She then could not be revived. At autopsy, widespread yellow aortic xanthomas were seen, with severe atheromatous narrowing of both coronary ostia (Figure 1). The right and left anterior descending arteries showed focal marked atheromatous narrowing. Grossly and microscopically, there were no specific myocardial changes. Atheromas were also seen on the surfaces of the mitral valve leaflets and within the pulmonary artery. Aortic lesions extended to the level of the superior mesenteric artery, and atheromas were present in the branches of the aortic arch. Serum cholesterol concentration from a sample of post-mortem blood was 13.0 mmol/L (503 mg/dL). Parental lipoprotein profiles were relatively normal. Genomic DNA was isolated from frozen liver, and sequencing of the LDLR, APOB, ARH, and ABCG5 genes revealed no mutations. However, a novel CϾG mutation was found at the second residue of codon nucleotide 107 in exon 3 of the ABCG8 gene, which predicted premature truncation of the protein product (S107X) (Figure 2). This mutation was absent from 400 normal chromosomes. The diagnosis of sitosterolemia, a rare autosomal recessive disorder of sterol absorption, was confirmed by documenting elevated serum total cholesterol and sitosterol concentrations in her sister, brother, and female cousin, aged 5, 4, and 8 years, respectively. Serum cholesterol was 10.8, 11.8, and 9.2 mmol/L (416, 455, and 356 mg/dL), respectively, and serum sitosterol concentrations were 282, 447, and 184 mg/L, respectively (reference range 0 to 10 mg/L) in these relatives, who were also shown to be homozygotes for S107X. The use of bile acid binding resins has greatly improved the lipoprotein profile in the 3 surviving homozygotes.