Rare genetic cerebrotendinous xanthomatosis (CTX) cases without cholestanol elevation but with prominent cholesterol-rich tendon xanthomas.

Cerebrotendinous xanthomatosis (CTX) is a rare inherited metabolic disease attributed to the mutation of the gene CYP27A1, resulting in sterol 27-hydroxylase deficiency characterized by deposition of cholestanol and cholesterol in several tissues, like the central nervous system and tendons. Furthermore, cataracts, gallstones, diarrhea and premature atherosclerosis have been reported. Nonetheless, clinical development is extremely heterogeneous in CTX. We report here two cases of CTX genetic alteration in the absence of cholestanol elevation in plasma and tendons but with prominent xanthomas. We propose that CTX may not be characteized by increased plasma cholestanol concentration due to alteration in the sterol 27-hydroxylase gene, but is a more complex pathology where there is significant genetic heterogeneity caused by various CYP27A1 mutations.

Plasma Campesterol Is Positively Associated with Carotid Plaques in Asymptomatic Subjects.

BACKGROUND: Increased cholesterol absorption and reduced synthesis are processes that have been associated with cardiovascular disease risk in a controversial way. However, most of the studies involving markers of cholesterol synthesis and absorption include conditions, such as obesity, diabetes, dyslipidemia, which can be confounding factors. The present study aimed at investigating the relationships of plasma cholesterol synthesis and absorption markers with cardiovascular disease (CVD) risk factors, cIMT (carotid intima-media thickness), and the presence of carotid plaques in asymptomatic subjects. METHODS: A cross-sectional study was carried out in 270 asymptomatic individuals and anthropometrical parameters, fasting plasma lipids, glucometabolic profiles, high-sensitivity C-reactive protein (hs-CRP), markers of cholesterol synthesis (desmosterol and lathosterol), absorption (campesterol and sitosterol), cIMT, and the presence of atherosclerotic plaques were analyzed. RESULTS: Among the selected subjects aged between 19 and 75 years, 51% were females. Age, body mass index, systolic and diastolic blood pressure, total cholesterol, non-HDL-C, triglycerides, glucose, and lathosterol/sitosterol ratios correlated positively with cIMT (p ≤ 0.05). Atherosclerotic plaques were present in 19% of the subjects. A direct association of carotid plaques with campesterol, OR = 1.71 (95% CI = 1.04-2.82, p ≤ 0.05) and inverse associations with both ratios lathosterol/campesterol, OR = 0.29 (CI = 0.11-0.80, p ≤ 0.05) and lathosterol/sitosterol, OR = 0.45 (CI = 0.22-0.95, p ≤ 0.05) were observed in univariate logistic regression analysis. CONCLUSIONS: The findings suggested that campesterol may be associated with atherosclerotic plaques and the lathosterol/campesterol or sitosterol ratios suggested an inverse association. Furthermore, synthesis and absorption of cholesterol are inverse processes, and the absorption marker, campesterol, may reflect changes in body cholesterol homeostasis with atherogenic potential.

Plasma lathosterol measures rates of cholesterol synthesis and efficiency of dietary phytosterols in reducing the plasma cholesterol concentration.

OBJECTIVES: Because the plasma campesterol/cholesterol ratio does not differ between groups that absorb different amounts of cholesterol, the authors investigated whether the plasma Phytosterols (PS) relate to the body's cholesterol synthesis rate measured as non-cholesterol sterol precursors (lathosterol). METHOD: The authors studied 38 non-obese volunteers (58±12 years; Low-Density Lipoprotein Cholesterol ‒ LDL-C ≥ 130 mg/dL) randomly assigned to consume 400 mL/day of soy milk (Control phase) or soy milk + PS (1.6 g/day) for four weeks in a double-blind, cross-over study. PS and lathosterol were measured in plasma by gas chromatography coupled to mass spectrophotometry. RESULTS: PS treatment reduced plasma total cholesterol concentration (-5.5%, p < 0.001), LDL-C (-7.6%, p < 0.001), triglycerides (-13.6%, p < 0.0085), and apolipoprotein B (apo B) (-6.3%, p < 0.008), without changing high density lipoprotein cholesterol (HDL-C concentration), but plasma lathosterol, campesterol and sitosterol expressed per plasma cholesterol increased. CONCLUSIONS: The lathosterol-to-cholesterol plasma ratio predicted the plasma cholesterol response to PS feeding. The highest plasma lathosterol concentration during the control phase was associated with a lack of response of plasma cholesterol during the PS treatment period. Consequently, cholesterol synthesis in non-responders to dietary PS being elevated in the control phase indicates these cases resist to further synthesis rise, whereas responders to dietary PS, having in the control phase synthesis values lower than non-responders, expand synthesis on alimentary PS. Responders absorb more PS than non-responders, likely resulting from responders delivering into the intestinal lumen less endogenous cholesterol than non-responders do, thus facilitating greater intestinal absorption of PS shown as increased plasma PS concentration.

Does eating eggs matter?

Dietary cholesterol is absorbed in proportion to the amount ingested, blocking its hepatic synthesis, increasing its biliary excretion, only slightly increasing production of bile acids while potentially raising the serum concentration of the atherogenic low-density lipoprotein. Humans lie midway between rats and rabbits that respond to dietary cholesterol, respectively, with high and low capacity to produce bile acids, and low or high capacity to raise blood cholesterol. There are regular studies exonerating as well as blaming dietary cholesterol as a cardiovascular risk factor, particularly in genetic hypercholesterolemic individuals. We then resorted at reviewing all meta-analyses on the subject but failed to reach at a clear conclusion useful in medical practice. Nevertheless, ingestion of the same amount of cholesterol results in wide variation in the amounts absorbed and in plasma lipoprotein profiles depending on poorly understood genetic factors. Several genetic conditions are capable of interfering with the absorption and synthesis of cholesterol. Hyperabsorption of dietary cholesterol elicits the accumulation of cholesterol in the liver and in plasma. In this regard, most cases of familial hypercholesterolemia that have a case of intestinal hyperabsorption of cholesterol also demonstrate the same defect. A practical useful suggestion is to measure for a few weeks the total serum cholesterol and its fractions at least three times before and during the intake of eggs that the candidate wishes to maintain in his usual dietary practice as an efficient procedure to identify those who respond with undesirable increases in serum cholesterol.

Does eating eggs matter?

ABSTRACT Dietary cholesterol is absorbed in proportion to the amount ingested, blocking its hepatic synthesis, increasing its biliary excretion, only slightly increasing production of bile acids while potentially raising the serum concentration of the atherogenic low-density lipoprotein. Humans lie midway between rats and rabbits that respond to dietary cholesterol, respectively, with high and low capacity to produce bile acids, and low or high capacity to raise blood cholesterol. There are regular studies exonerating as well as blaming dietary cholesterol as a cardiovascular risk factor, particularly in genetic hypercholesterolemic individuals. We then resorted at reviewing all meta-analyses on the subject but failed to reach at a clear conclusion useful in medical practice. Nevertheless, ingestion of the same amount of cholesterol results in wide variation in the amounts absorbed and in plasma lipoprotein profiles depending on poorly understood genetic factors. Several genetic conditions are capable of interfering with the absorption and synthesis of cholesterol. Hyperabsorption of dietary cholesterol elicits the accumulation of cholesterol in the liver and in plasma. In this regard, most cases of familial hypercholesterolemia that have a case of intestinal hyperabsorption of cholesterol also demonstrate the same defect. A practical useful suggestion is to measure for a few weeks the total serum cholesterol and its fractions at least three times before and during the intake of eggs that the candidate wishes to maintain in his usual dietary practice as an efficient procedure to identify those who respond with undesirable increases in serum cholesterol.

The Plasma Distribution of Non-cholesterol Sterol Precursors and Products of Cholesterol Synthesis and Phytosterols Depend on HDL Concentration.

Non-cholesterol sterols are transported in plasma lipoproteins and are consequently important in cholesterol metabolism. We investigated the distribution of non-cholesterol sterol precursors of cholesterol synthesis (NCSPCS), oxysterols, and phytosterols in lipoproteins of healthy subjects differing according to HDL-Cholesterol (HDL-C) plasma levels. Elevated NCSPCS (desmosterol, lathosterol) in the High HDL group suggests that HDL exports these sterols from cells, but not the cholesterol metabolite 24-OHC which was higher in the Low HDL group than in the High HDL group. 27-hydroxycholesterol (27OH-C) plasma levels did not differ between groups. Percentage of NCSPCS and phytosterols predominates in LDL, but did not differ between groups. Thirty percent of desmosterol and lathosterol are present in HDL, with the High HDL group carrying higher percentage of these sterols. A high percentage of campesterol and sitosterol in HDL suggests that phytosterols are absorbed by enterocytes, and that HDL could be a marker of the ABCA1/ApoA1 intestinal activity.

Cholesterol metabolism in aging simultaneously altered in liver and nervous system.

In humans, aging, triggers increased plasma concentrations of triglycerides, cholesterol, low-density lipoproteins and lower capacity of high-density lipoproteins to remove cellular cholesterol. Studies in rodents showed that aging led to cholesterol accumulation in the liver and decrease in the brain with reduced cholesterol synthesis and increased levels of cholesterol 24-hydroxylase, an enzyme responsible for removing cholesterol from the brain. Liver diseases are also related to brain aging, inducing changes in cholesterol metabolism in the brain and liver of rats. It has been suggested that late onset Alzheimer's disease is associated with metabolic syndrome. Non-alcoholic fatty liver is associated with lower total brain volume in the Framingham Heart Study offspring cohort study. Furthermore, disorders of cholesterol homeostasis in the adult brain are associated with neurological diseases such as Niemann-Pick, Alzheimer, Parkinson, Huntington and epilepsy. Apolipoprotein E (apoE) is important in transporting cholesterol from astrocytes to neurons in the etiology of sporadic Alzheimer's disease, an aging-related dementia. Desmosterol and 24S-hydroxycholesterol are reduced in ApoE KO hypercholesterolemic mice. ApoE KO mice have synaptic loss, cognitive dysfunction, and elevated plasma lipid levels that can affect brain function. In contrast to cholesterol itself, there is a continuous uptake of 27- hydroxycholesterol in the brain as it crosses the blood-brain barrier and this flow can be an important link between intra- and extracerebral cholesterol homeostasis. Not surprisingly, changes in cholesterol metabolism occur simultaneously in the liver and nervous tissues and may be considered possible biomarkers of the liver and nervous system aging.

Plasma lathosterol measures rates of cholesterol synthesis and efficiency of dietary phytosterols in reducing the plasma cholesterol concentration

Abstract Objectives Because the plasma campesterol/cholesterol ratio does not differ between groups that absorb different amounts of cholesterol, the authors investigated whether the plasma Phytosterols (PS) relate to the body's cholesterol synthesis rate measured as non-cholesterol sterol precursors (lathosterol). Method The authors studied 38 non-obese volunteers (58±12 years; Low-Density Lipoprotein Cholesterol ‒ LDL-C ≥ 130 mg/dL) randomly assigned to consume 400 mL/day of soy milk (Control phase) or soy milk + PS (1.6 g/day) for four weeks in a double-blind, cross-over study. PS and lathosterol were measured in plasma by gas chromatography coupled to mass spectrophotometry. Results PS treatment reduced plasma total cholesterol concentration (-5.5%, p < 0.001), LDL-C (-7.6%, p < 0.001), triglycerides (-13.6%, p < 0.0085), and apolipoprotein B (apo B) (-6.3%, p < 0.008), without changing high density lipoprotein cholesterol (HDL-C concentration), but plasma lathosterol, campesterol and sitosterol expressed per plasma cholesterol increased. Conclusions The lathosterol-to-cholesterol plasma ratio predicted the plasma cholesterol response to PS feeding. The highest plasma lathosterol concentration during the control phase was associated with a lack of response of plasma cholesterol during the PS treatment period. Consequently, cholesterol synthesis in non-responders to dietary PS being elevated in the control phase indicates these cases resist to further synthesis rise, whereas responders to dietary PS, having in the control phase synthesis values lower than non-responders, expand synthesis on alimentary PS. Responders absorb more PS than non-responders, likely resulting from responders delivering into the intestinal lumen less endogenous cholesterol than non-responders do, thus facilitating greater intestinal absorption of PS shown as increased plasma PS concentration.

Cholesterol-Ester Transfer Protein Alters M1 and M2 Macrophage Polarization and Worsens Experimental Elastase-Induced Pulmonary Emphysema.

Cholesterol-ester transfer protein (CETP) plays a role in atherosclerosis, the inflammatory response to endotoxemia and in experimental and human sepsis. Functional alterations in lipoprotein (LP) metabolism and immune cell populations, including macrophages, occur during sepsis and may be related to comorbidities such as chronic obstructive pulmonary disease (COPD). Macrophages are significantly associated with pulmonary emphysema, and depending on the microenvironment, might exhibit an M1 or M2 phenotype. Macrophages derived from the peritoneum and bone marrow reveal CETP that contributes to its plasma concentration. Here, we evaluated the role of CETP in macrophage polarization and elastase-induced pulmonary emphysema (ELA) in human CETP-expressing transgenic (huCETP) (line 5203, C57BL6/J background) male mice and compared it to their wild type littermates. We showed that bone marrow-derived macrophages from huCETP mice reduce polarization toward the M1 phenotype, but with increased IL-10. Compared to WT, huCETP mice exposed to elastase showed worsened lung function with an increased mean linear intercept (Lm), reflecting airspace enlargement resulting from parenchymal destruction with increased expression of arginase-1 and IL-10, which are M2 markers. The cytokine profile revealed increased IL-6 in plasma and TNF, and IL-10 in bronchoalveolar lavage (BAL), corroborating with the lung immunohistochemistry in the huCETP-ELA group compared to WT-ELA. Elastase treatment in the huCETP group increased VLDL-C and reduced HDL-C. Elastase-induced pulmonary emphysema in huCETP mice promotes lung M2-like phenotype with a deleterious effect in experimental COPD, corroborating the in vitro result in which CETP promoted M2 macrophage polarization. Our results suggest that CETP is associated with inflammatory response and influences the role of macrophages in COPD.

Plasma Non-cholesterol Sterols as Markers of Cholesterol Synthesis and Intestinal Absorption: A Critical Review.

Plasma concentrations of phytosterols and non-cholesterol sterol precursors of cholesterol synthesis have been used as markers of intestinal cholesterol absorption and synthesis in inherited and secondary dyslipidemias and in population-based investigations to evaluate the risk for cardiovascular disease, respectively. The method aims at replacing initial research procedures such as the use of stable isotopes associated with fecal steroid balance, which are limited by the high cost and tedious procedures. However, we show in this review that numerous results obtained with serum sterol measurements are contradictory. In this regard, the following points are discussed: 1) how phytosterols relate to atherosclerosis considering that defects in biliary output or in the transport of phytosterols from the intestinal mucosa back into the intestinal lumen provide increased content of phytosterols and other sterols in plasma and tissues, thus not allowing to conclude that their presence in arteries and atheromas represents the etiology of atherosclerosis; 2) serum non-cholesterol sterols as markers of cholesterol synthesis and absorption, such as cholestanol, present discrepant results, rendering them often inadequate to identify cases of coronary artery disease as well as alterations in the whole body cholesterol metabolism; 3) such methods of measurement of cholesterol metabolism are confounded by factors like diabetes mellitus, body weight and other pathologies including considerable hereditary hyperlipidemias biological variabilities that influence the efficiency of synthesis and intestinal absorption of cholesterol.

The coronary artery calcium score is linked to plasma cholesterol synthesis and absorption markers: Brazilian Longitudinal Study of Adult Health.

It is controversial whether atherosclerosis is linked to increased intestinal cholesterol absorption or synthesis in humans. The aim of the present study was to relate atherosclerosis to the measurements of plasma markers of cholesterol synthesis (desmosterol, lathosterol) and absorption (campesterol, sitosterol). In healthy male (n=344), non-obese, non-diabetics, belonging to the city of São Paulo branch of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), we measured in plasma these non-cholesterol sterol markers, together with their anthropometric, dietary parameters, traditional atherosclerotic risk factors, and blood chemistry, coronary arterial calcium score (CAC), and ultrasonographically measured common carotid artery intima-media thickness (CCA-IMT). Cases with CAC>zero had the following parameters higher than cases with CAC = zero: age, waist circumference (WC), plasma total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and non-high density lipoprotein-cholesterol (non HDL-C). Plasma desmosterol and campesterol, duly corrected for TC, age, body mass index (BMI), waist circumference (WC), hypertension, smoking, and the homeostasis model assessment-insulin resistance (HOMA-IR) correlated with CAC, but not with CCA-IMT. The latter related to increased age, BMI, waist circumference (WC), and systolic blood pressure (SBP). Plasma HDL-C concentrations did not define CAC or CCA-IMT degrees, although in relation to the lower tertile of HDL-C in plasma the higher tertile of HDL-C had lower HOMA-IR and concentration of a cholesterol synthesis marker (desmosterol). Present work indicated that increased cholesterol synthesis and absorption represent primary causes of CAD, but not of the common carotid artery atherosclerosis.

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.

Phytosterols Supplementation Reduces Endothelin-1 Plasma Concentration in Moderately Hypercholesterolemic Individuals Independently of Their Cholesterol-Lowering Properties.

Experimental and clinical studies have demonstrated the effect of phytosterols (PS) on reducing plasma levels of cholesterol and LDL-c, but the effects of plant sterols beyond cholesterol-lowering are still questionable. Since inflammation and endothelial dysfunction are involved in the pathogenesis of atherosclerosis, this study aims to evaluate the effect of PS on biomarkers involved in atherosclerosis progression and whether these effects are independent of alterations in plasma LDL-c levels. Thirty-eight moderately hypercholesterolemic volunteers (58 ± 12 years; LDL-c ≥ 130 mg/dL) were randomly assigned to consume 400 mL/day of soy milk or soy milk + PS (1.6 g/day) for 4 weeks in a double-blind, placebo-controlled, cross-over study. Blood samples were collected and lipid profiles and biomarkers for inflammation and endothelial dysfunction determined. The results showed that PS treatment reduced endothelin-1 plasma concentration by 11% (p = 0.02) independently of variations in plasma levels of LDL-c. No alterations were observed regarding fibrinogen, IL-6, hs-CRP, SAA, TNFα, or VCAM-1 between placebo and PS-treated groups. Furthermore, PS reduced total plasma cholesterol concentration (-5,5%, p < 0.001), LDL-c (-6.4%, p < 0.05), triglycerides (-8.3%, p < 0.05), and apo B (-5.3%, p < 0.05), without changing HDL-c concentration (p > 0.05). Therefore, PS supplementation effectively lowers endothelin-1 independently of the reductions in plasma levels of LDL-c, contributing to the comprehension of the effect of plant sterols on endothelial function and prevention of cardiovascular diseases.

Phytosterol containing diet increases plasma and whole body concentration of phytosterols in apoE-KO but not in LDLR-KO mice.

Phytosterol metabolism is unknown in the hypercholesterolemia of genetic origin. We investigated the metabolism of phytosterols in a cholesterol-free, phytosterol-containing standard diet in hypercholesterolemic mice knockouts for low density lipoprotein receptor (LDLR) and apolipoprotein E (apoE) mice compared to wild-type mice (controls). Phytosterols were measured in mice tissues by GCMS. ApoE-KO mice absorbed less phytosterols than LDLR-KO and the latter absorbed less phytosterols than control mice, because the intestinal campesterol content was low in both KO mice, and sitosterol was low in the intestine in apoE-KO mice as compared to LDLR-KO mice. Although the diet contained nine times more sitosterol than campesterol, the concentration of sitosterol was lower than that of campesterol in plasma in LDLR-KO, and in the liver in controls and in LDLR-KO, but only in apoE-KO. On the other hand, in the intestine sitosterol was higher than campesterol in controls, and in LDLR-KO but with a tendency only in apoE-KO. Because of the high dietary supply of sitosterol, sitosterol was better taken up by the intestine than campesterol, but the amount of sitosterol was lower than that of campesterol in the liver, while in the whole body the amounts of these phytosterols do not differ from each other. Therefore, via intestinal lymph less sitosterol than campesterol was transferred to the body. However, as compared to controls, in apoE-KO mice, but not in LDLR-KO mice, the increase in campesterol and sitosterol in plasma and in the whole body indicating that apoE-KO mice have a marked defect in the elimination of both phytosterols from the body.

Molecular Pathways Underlying Cholesterol Homeostasis.

Cholesterol is an essential molecule that exerts pleiotropic actions. Although its presence is vital to the cell, its excess can be harmful and, therefore, sustaining cholesterol homeostasis is crucial to maintaining proper cellular functioning. It is well documented that high plasma cholesterol concentration increases the risk of atherosclerotic heart disease. In the last decades, several studies have investigated the association of plasma cholesterol concentrations and the risk of cardiovascular diseases as well as the signaling pathways involved in cholesterol homeostasis. Here, we present an overview of several mechanisms involved in intestinal cholesterol absorption, the regulation of cholesterol synthesis and uptake. We also discuss the importance of reverse cholesterol transport and transintestinal cholesterol transport to maintain cholesterol homeostasis and prevent atherosclerosis development. Additionally, we discuss the influence of dietary cholesterol on plasma cholesterol concentration and the new recommendations for cholesterol intake in a context of a healthy dietary pattern.

Decreased content, rate of synthesis and export of cholesterol in the brain of apoE knockout mice.

Apolipoprotein E knockout (apoE-KO) mice present synaptic loss, cognitive dysfunction, and high plasma lipid levels that may affect brain function simulating Alzheimer disease. Plasma and brain sterols were measured in apoE-KO and in wild type control mice on a cholesterol-free, phytosterol-containing diet by gas chromatography coupled to a mass spectrometer. Plasma cholesterol and phytosterols (campesterol and sitosterol) were higher in apoE-KO compared to control mice. Cholesterol precursors (desmosterol and lathosterol) were not detected in plasma of control mice but were present in apoE-KO mice. In the brain amounts of cholesterol, desmosterol, campesterol and 24-hydroxycholesterol were significantly lower in apoE-KO than in controls. There is a tendency in apoE-KO for lower values of 7α-hydroxycholesterol and 7ß-hydroxycholesterol. Cholesterol content, synthesis rates (desmosterol) and export of 24-hydroxycholesterol are reduced in the brain of the severe hypercholesterolemic apoE-KO mice.

Low-sodium diet induces atherogenesis regardless of lowering blood pressure in hypertensive hyperlipidemic mice.

This study investigated the influence of sodium restriction and antihypertensive drugs on atherogenesis utilizing hypertensive (H) low-density lipoprotein-receptor knockout mice treated or not with losartan (Los) or hydralazine (Hyd) and fed low-sodium (LS) or normal-sodium (NS) chow. Despite reducing the blood pressure (BP) of H-LS mice, the LS diet caused arterial lipid infiltration due to increased plasma total cholesterol (TC) and triglycerides (TG). Los and Hyd reduced the BP of H-LS mice, and Los effectively prevented arterial injury, likely by reducing plasma TG and nonesterified fatty acids. Aortic lipid infiltration was lower in Los-treated H-LS mice (H-LS+Los) than in normotensive (N)-LS and H-LS mice. Aortic angiotensin II type 1 (AT1) receptor content was greater in H-NS than H-LS mice and in H-LS+Hyd than H-LS+Los mice. Carboxymethyl-lysine (CML) and receptor for advanced glycation end products (RAGE) immunostaining was greater in H-LS than H-NS mice. CML and RAGE levels were lower in LS animals treated with antihypertensive drugs, and Hyd enhanced the AT1 receptor level. Hyd also increased the gene expression of F4/80 but not tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, IL-10, intercellular adhesion molecule-1 or cluster of differentiation 66. The novelty of the current study is that in a murine model of simultaneous hypertension and hyperlipidemia, the pleiotropic effect of chronic, severe sodium restriction elicited aortic damage even with reduced BP. These negative effects on the arterial wall were reduced by AT1 receptor antagonism, demonstrating the influence of angiotensin II in atherogenesis induced by a severely LS diet.

CETP Lowers TLR4 Expression Which Attenuates the Inflammatory Response Induced by LPS and Polymicrobial Sepsis.

Sepsis is a systemic inflammatory response to infection eliciting high mortality rate which is a serious health problem. Despite numerous studies seeking for therapeutic alternatives, the mechanisms involved in this disease remain elusive. In this study we evaluated the influence of cholesteryl ester transfer protein (CETP), a glycoprotein that promotes the transfer of lipids between lipoproteins, on the inflammatory response in mice. Human CETP transgenic mice were compared to control mice (wild type, WT) after polymicrobial sepsis induced by cecal ligation and puncture (CLP), aiming at investigating their survival rate and inflammatory profiles. Macrophages from the peritoneal cavity were stimulated with LPS in the presence or absence of recombinant CETP for phenotypic and functional studies. In comparison to WT mice, CETP mice showed higher survival rate, lower IL-6 plasma concentration, and decreased liver toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH) protein. Moreover, macrophages from WT mice to which recombinant human CETP was added decreased LPS uptake, TLR4 expression, NF-κB activation and IL-6 secretion. This raises the possibility for new therapeutic tools in sepsis while suggesting that lowering CETP by pharmacological inhibitors should be inconvenient in the context of sepsis and infectious diseases.

The controversy over the use of cholesteryl ester transfer protein inhibitors: is there some light at the end of the tunnel?

BACKGROUND: According to epidemiological studies, there is no clear relationship between the plasma cholesteryl ester transfer protein (CETP) concentration and the development of atherosclerosis in human populations. Although some studies suggest that increased CETP activity relates to undesirable profiles of plasma lipoproteins, promoting an anti-atherogenic plasma lipoprotein profile by drugs that inhibit CETP has not succeeded in preventing atherosclerosis in humans. MATERIALS AND METHODS: This review describes 28 investigations in human populations dealing with plasma CETP, 11 in mice that express human CETP and seven in animals (six in rabbits and one in mice) in which plasma CETP activity was inhibited by drugs. RESULTS: Present review shows that models in mice expressing human CETP are not illuminating because they report increase as well reduction of atherosclerosis. However, investigations in rabbits and mice that develop severe hypercholesterolaemia clearly indicate that impairment of the plasma CETP activity elicits protection against the development of atherosclerosis; in all of these experiments are attained substantial reductions of the atherogenic lipoproteins, namely, plasma apoB containing lipoproteins. CONCLUSION: These models are strong indicators that the benefit in preventing atherosclerosis should be earned in cases of hyperlipidemia by CETP inhibitors.