Cholesterol metabolism in mice models of genetic hypercholesterolemia.

Monogenic familial hypercholesterolemia is characterized by impaired cellular uptake of apolipoprotein B containing lipoproteins. However, its consequences on whole-body cholesterol metabolism are unclear. We investigated cholesterol metabolism in wild-type mice (control) and in knockout (KO) mice for the low-density lipoprotein receptor (LDLR-KO) and for apolipoprotein E (apoE-KO) containing the genetic basis of the C57BL/6J mice, under a cholesterol-free diet. Cholesterol and "non-cholesterol" sterols (cholestanol, desmosterol, and lathosterol) were measured in plasma, tissues, as well as in feces as cholesterol and its bacterial modified products (neutral sterols) using gas chromatography/mass spectrometry, and bile acids were measured by an enzymatic method. Compared to controls, LDLR-KO mice have elevated plasma and whole-body cholesterol concentrations, but total fecal sterols are not modified, characterizing unaltered body cholesterol synthesis together with impaired body cholesterol excretion. ApoE-KO mice presented the highest concentrations of plasma cholesterol, whole-body cholesterol, cholestanol, total fecal sterols, and cholestanol, compatible with high cholesterol synthesis rate; the latter seems attributed to elevated body desmosterol (Bloch cholesterol synthesis pathway). Nonetheless, whole-body lathosterol (Kandutsch-Russel cholesterol synthesis pathway) decreased in both KO models, likely explaining the diminished fecal bile acids. We have demonstrated for the first time quantitative changes of cholesterol metabolism in experimental mouse models that explain differences between LDLR-KO and apoE-KO mice. These findings contribute to elucidate the metabolism of cholesterol in human hypercholesterolemia of genetic origin.

Is there an association between hypercholesterolemia and depression? Behavioral evidence from the LDLr(-/-) mouse experimental model.

Although epidemiological studies have reported an association between hypercholesterolemia and mood disorders, there is a lack of data regarding depressive-like behavior in animal models of hypercholesterolemia. To address these questions, we assessed depressive-like behavior and hippocampal and cortical monoaminergic metabolism in three-month-old, low-density lipoprotein receptor knockout (LDLr(-/-)) and C57BL/6 wild-type mice. The LDLr(-/-) mice exhibited depressive-like behavior in the sucrose preference test, splash test, and tail suspension test. Increased monoamine oxidase (MAO) A and B activity was evidenced in the hippocampus of LDLr(-/-) mice. Furthermore, to address whether or not cholesterol modulates MAO activity, we exposed SH-SY5Y human neuroblastoma cells to human isolated low-density lipoprotein (LDL). Notably, LDL increased the activity of MAO-A and stimulated the reactive species generation in vitro. These findings indicate that depressive-like behavior in hypercholesterolemic mice is accompanied by alterations in the monoaminergic metabolism, providing new evidence about the association between hypercholesterolemia and depression.

Efeitos da administração de eritropoietina na dislipidemia e na hipertrofia ventricular esquerda de camundongos hiperlipidêmicos / Effects of administration of the erythropoietin in dyslipidemia and left ventricular hypertrophy of hyperlipidemic mice

O principal objetivo deste trabalho foi avaliar os efeitos da eritropoietina (EPO) no perfil lipídico e na hipertrofia ventricular esquerda (HVE) de camundongos LDLr-/- alimentados com dieta hiperlipídica, Foram utilizados vinte e quatro camundongos LDLr-/-, machos, 3 meses de idade, equinumericamente divididos em 3 grupos: Grupo S, alimentados com dieta padrão, Grupo HL, alimentados com dieta hiperlipídica (20% de gordura total e 1,25% de colesterol, 0,5 % ácido cólico), Grupo HL+EPO, alimentados com dieta hiperlipídica e tratados com EPO na dose semanal de 200UI/kg via subcutânea, Após 75 dias de experimento foram avaliadas a desenvoltura da HVE e as concentrações séricas de glicose, triglicérides (TG), colesterol total (CT) e de lipoproteínas de baixa densidade (LDL), de muita baixa densidade (VLDL), e de alta densidade (HDL) além da razão entre a massa ventricular esquerda e a massa total do animal: massa ventricular (mg)/massa do animal(g), O protocolo experimental foi aprovado pelo Comitê de Ética Experimental da Universidade sob o número 13A/2010, Ao final do período experimental, os camundongos do grupo HL apresentaram desenvolvimento de HVE com aumento nas concentrações séricas de CT, LDL, VLDL, TG e glicose e redução do HDL, quando comparados com parâmetros dos camundongos do grupo S, O uso da EPO pelo grupo HL+EPO aumentou significativamente (p<0,05) as concentrações séricas do HDL, quando comparados com o grupo HL, e preveniu a HVE, Além disso, reduziu as concentrações de CT, LDL e glicose (p<0,05), Entretanto, a EPO não foi eficiente em impedir a hipertrigliceridemia e tão pouco foi capaz de reduzir as concentrações de VLDL induzidas pela dieta HL, Em conclusão, a EPO apresentou alguns efeitos cardioprotetores, prevenindo a HVE bem como corrigindo algumas das variáveis bioquímicas induzidas pela dieta HL, Estes efeitos podem estar em parte, relacionados ao aumento das concentrações plasmáticas de HDL...

The main purpose of this work was to evaluate the effects of erythropoietin (EPO) on the lipid profile and in left ventricular hypertrophy (LVH) in mice LDLr-/-, fed a high fat diet. Were used twenty-four mice LDLr- / -, male, 3 months old, proportionally divided in 3 groups: S Group, fed with standard diet; HL Group, fed with high fat diet (20% fat total and 1.25% cholesterol, 0.5% cholic acid); HL + EPO Group, fed with high-fat diet and treated with EPO on weekly dose of 200UIkg, subcutaneously. After 75 days of experiment the development of LVH, serum concentrations of glucose, triglycerides (TG), total cholesterol (TC), and low, very low and high density lipoprotein (LDL, VLDL and HDL, respectively) in addition to the left ventricular mass ratio and the total mass of the animal (ventricular mass(mg)/total animal mass(g)) were evaluated. The experimental protocol was approved by the University Ethics Committee of the Experimental Studies under the number 13A/2010. At the end of the trial period, the mice of the HL presented development of LVH with increase in serum concentrations of CT, LDL, VLDL, TG and glucose and a decreased of HDL concentrations, when compared with parameters of mice of the Group S. The use of EPO by HL+EPO group increased serum concentrations of HDL, compared with the HL group (p<0,05) and prevented LVH. In addition, reduced the serum concentrations of TC, LDL, and glucose (p<0,05). However, EPO was not efficient in preventing the hypertriglyceridemia and still, wasn?t able to reduce VLDL concentrations induced by the diet HL. In conclusion, the EPO presented some cardio protective effects, preventing the HVE as well as correcting some of the biochemical variables diet HL-induced. These effects may be, in part, related to increased plasma concentrations of HDL...

Wild rice (Zizania palustris L.) prevents atherogenesis in LDL receptor knockout mice.

OBJECTIVES: Dietary modifications including healthy eating constitute one of the first line strategies for prevention and treatment of cardiovascular disease (CVD) risk factors including high cholesterol and atherosclerosis. The purpose of the present study was to investigate the potential cardiovascular benefits of wild rice in male and female LDL-receptor-deficient (LDLr-KO) mice. METHODS: Wild rice was used to create a semi-synthetic diet containing approximately 60% of total energy from carbohydrate. Two other experimental diets were similar in macronutrient composition, but containing either white rice or commercial carbohydrate sources. All diets were supplemented with 0.06% (w/w) dietary cholesterol. The mice were divided into six experimental groups and fed with these diets over 24 weeks. RESULTS: Consumption of wild rice significantly reduced the size and severity of atherosclerotic lesions in the aortic roots of male and female mice by 71 and 61% respectively, compared to the control group of the same gender. This effect was associated with significant reductions of plasma cholesterol levels by 15 and 40%, low density lipoprotein (LDL) levels by 12 and 42%, and very low density lipoprotein (VLDL) levels by 35 and 75% respectively, in male and female mice compared to the control group of the same gender. Increased fecal cholesterol excretion of up to 34% was also noted, compared to the control group of the same gender. However, the antiatherogenic effect of wild rice was not associated with increased superoxide dismutase (SOD) and catalase (CAT) activities. CONCLUSION: Current data suggest that cholesterol-lowering effects of wild rice may be the main factor for the prevention of atherogenesis in LDLr-KO mice. Additional studies are needed to understand the mechanism of action.