High Dietary Cholesterol Intake Research Articles

Statins in the Cause and Prevention of Cancer: Confounding by Indication and Mediation by Rhabdomyolysis and Phosphate Toxicity.

Statins are drugs used in cardiovascular pharmacotherapy to decrease hypercholesterolemia and lower the risk of atherosclerosis. Statins also increase the risk of rhabdomyolysis, which is often minimized in comparison with large relative risk reductions of cardiovascular disease reported in clinical trials. By contrast, absolute risk reductions of cardiovascular disease are often clinically insignificant and unreported in statin clinical trials. Additionally, cytotoxic effects of statins inhibit cancer cell proliferation and reduce cancer risk, but other studies found that statins are carcinogenic. Due to an inverse association between incidence of cancer and atherosclerosis, the indication to prescribe statins likely biases the association of statins with cancer prevention. Dietary patterns associated with atherosclerosis and cancer contain inverse amounts of cholesterol and phosphate, an essential mineral that stimulates tumorigenesis. Accordingly, lower cancer risk is associated with high dietary cholesterol intake and increased risk of atherosclerosis. Furthermore, serum is exposed to excessive inorganic phosphate that could increase cancer risk as rhabdomyolysis induced by statins releases phosphate from skeletal muscle breakdown. Increased risk of comorbid conditions associated with statins may share the mediating factor of phosphate toxicity. More research is warranted on statins in the cause and prevention of cancer.

Factors influencing the association between depressive symptoms and cardiovascular disease in US population

Cardiovascular disease (CVD) and depression are common diseases that lead to adverse health outcomes. Depressive Symptoms may be a risk factor for CVD. But few studies focused on the impact of socioeconomic factors, common medical history and dietary intake about this association. This study analyzed National Health and Nutrition Examination Survey (NHANES) 2007–2016. Complex sampling-weighted logistic regression models were used to compare the odds ratios (ORs) of CVD in participants with different depressive symptoms. 11,516 NHANES participants aged ≥ 40 years were included in the final analysis, of whom 1842 had CVD. Compared with participants with no/minimal depression, participants with mild, moderate, and moderately severe/severe depression had OR values of 1.25 (95% CI 1.01–1.54), 1.98 (95% CI 1.32–2.96), and 2.41 (95% CI 1.63–3.57). The association of depressive symptoms with CVD follow a dose-dependent pattern. The interactions of depressive symptoms with gender (Interaction P = 0.009), diabetes (Interaction P = 0.010), household income level (Interaction P = 0.002), dietary cholesterol intake (Interaction P = 0.017) on CVD were observed. More severe depressive symptoms are associated with increased risk of CVD in US population. The association may be more pronounced in the female population, population with diabetes, low family income level, or high dietary cholesterol intake.

Contrasting Evidences Between High Cholesterol Levels and The Risk of Cardiovascular Disease: A Review

Introduction: The cholesterol hypothesis had been kept alive for decades by reviewers who used statistics that excluded the results from unsuccessful trials and ignored numerous contradictory observations. High dietary cholesterol intake had been associated with development of cardiovascular diseases (CVD) and mortality, for over several decades, without a direct link between the CVD and high serum cholesterol level. Hence, people avoided healthy cholesterol-rich diets due to the fear of developing CVD. The relationship between elevated plasma cholesterol and CVD and criteria for appropriate methods for screening patients with elevated cholesterol had remained a source of medical debates. Lack of decrease in overall mortality rates in patients without clinical coronary disease in whom aggressive lowering of cholesterol was achieved might have contributed to the lack of consensus on this most important issue.
 Methodology: With information derived from search engines, such as Elsevier, Springer, PubMed, Science Direct, Medline, Google Scholar and a library search for articles published in peer-reviewed journals.
 Results: Several research results showed that association between total serum cholesterol, its components and CVD is weak, absent or inverse implying that consuming healthy high cholesterol diets may not be harmful to health.
 Conclusion: This review provides evidence contrasting the links between elevated plasma cholesterol and CVD, and demonstrated that elevated cholesterol concentrations, rather, improve quality of life and life expectancy. In addition, most prevalent methods for cholesterol quantification in biological samples and foods, utilizing new technologies, such as Ambient Ionization Mass Spectrometry are summarized, along with other components of cholesterol.
 Keywords: Cholesterol, CVD, Quantification

Study protocol for a 15-week randomised controlled trial assessing the independent effects of high-cholesterol and high-saturated fat diets on LDL cholesterol

IntroductionPrevious research has associated high dietary cholesterol intake with raised low-density lipoprotein cholesterol (LDL-C) and thus increased risk for cardiovascular disease (CVD). Emerging research suggests that it is saturated fat,...

Laminarin Reduces Cholesterol Uptake and NPC1L1 Protein Expression in High-Fat Diet (HFD)-Fed Mice.

Aberrantly high dietary cholesterol intake and intestinal cholesterol uptake lead to dyslipidemia, one of the risk factors for cardiovascular diseases (CVDs). Based on previous studies, laminarin, a polysaccharide found in brown algae, has hypolipidemic activity, but its underlying mechanism has not been elucidated. In this study, we investigated the effect of laminarin on intestinal cholesterol uptake in vitro, as well as the lipid and morphological parameters in an in vivo model of high-fat diet (HFD)-fed mice, and addressed the question of whether Niemann-Pick C1-like 1 protein (NPC1L1), a key transporter mediating dietary cholesterol uptake, is involved in the mechanistic action of laminarin. In in vitro studies, BODIPY-cholesterol-labeled Caco-2 cells were examined using confocal microscopy and a fluorescence reader. The results demonstrated that laminarin inhibited cholesterol uptake into Caco-2 cells in a concentration-dependent manner (EC50 = 20.69 μM). In HFD-fed C57BL/6J mice, laminarin significantly reduced the serum levels of total cholesterol (TC), total triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). It also decreased hepatic levels of TC, TG, and total bile acids (TBA) while promoting the excretion of fecal cholesterol. Furthermore, laminarin significantly reduced local villous damage in the jejunum of HFD mice. Mechanistic studies revealed that laminarin significantly downregulated NPC1L1 protein expression in the jejunum of HFD-fed mice. The siRNA-mediated knockdown of NPC1L1 attenuated the laminarin-mediated inhibition of cholesterol uptake in Caco-2 cells. This study suggests that laminarin significantly improves dyslipidemia in HFD-fed mice, likely by reducing cholesterol uptake through a mechanism that involves the downregulation of NPC1L1 expression.

The effects of dietary linoleic acid on reducing serum cholesterol and atherosclerosis development are nullified by a high-cholesterol diet in male and female apoE-deficient mice.

Linoleic acid (LA) has a two-sided effect with regard to serum cholesterol-lowering and pro-inflammation, although whether this fatty acid reduces serum cholesterol and the development of atherosclerosis under high-cholesterol conditions has yet to be ascertained. In this study, we examine the effects of dietary LA on reducing serum cholesterol and atherosclerosis development under high-cholesterol conditions. Male and female apoE-deficient (ApoE-/-) mice were fed AIN-76-based diets containing 10% SFA and 0·04 % cholesterol, 10% LA and 0·04% low cholesterol (LALC), or 10% LA and 0·1% high cholesterol (LAHC) for 9 weeks. The results revealed significant reduction in serum cholesterol levels and aortic lesions with increasing levels of pro-inflammatory biomarkers (urinary isoprostane and aortic MCP-1 mRNA) in male and female LALC groups compared with those in the SFA groups (P < 0·05). Furthermore, whereas there were significant increases in the serum cholesterol levels and aortic lesions (P < 0·05), there was no difference in aortic MCP-1 mRNA levels in male and female LAHC groups compared with those in the LALC groups. A high-dietary intake of cholesterol eliminated the serum cholesterol-lowering activity of LA but had no significant effect on aortic inflammation in either male or female ApoE-/- mice. The inhibitory effect of LA on arteriosclerosis is cancelled by a high-cholesterol diet due to a direct increase in serum cholesterol levels. Accordingly, serum cholesterol levels might represent a more prominent pathogenic factor than aortic inflammation in promoting the development of atherosclerosis.

Dietary Cholesterol‐Induced Gut Microbes Drive Nonalcoholic Fatty Liver Disease Pathogenesis in a Murine Model

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are hepatic manifestations of metabolic syndrome and major indications for liver transplantation. Western diet contributes to disease pathogenesis, partially mediated through the gut microbiome, yet mechanisms remain elusive. Human epidemiological studies identified high dietary cholesterol intake as a NAFLD risk factor and it is essential to drive disease in murine models, yet little is known about its role in reshaping gut microbiota. Using the fast food (FF) diet murine model in germ‐free (GF) mice completely devoid of all microbes and their conventionally‐raised (control) counterparts harboring complex microbiomes, we hypothesized high dietary cholesterol‐induced gut microbiota impact NAFLD onset, progression, and severity.Male C57Bl/6 age‐matched GF and control mice were fed 1 of 4 semi‐purified diets: low‐fat (LF); high fat (HF); FF + 0.2% high cholesterol (FFHC); FF + 2% very high cholesterol (FFVHC) for 8 or 24 weeks. Fecal gut microbiota profiles were tracked over time via Illumina MiSeq 16S rRNA gene amplicon sequencing. Serum alanine transaminase (ALT) and lipopolysaccharide binding protein (LBP, an indicator of gut barrier function) were measured throughout the study. Livers were collected for histology and Illumina NovaSeq RNA‐sequencing.Despite equal caloric intake between GF and controls across diets, significant weight gain and increased liver weight to body weight ratios (P&lt;0.05) were observed only in control mice fed FF diets. GF mice were largely protected from disease, with no elevation in plasma ALT, LBP, or histology‐based NAFLD activity score (NAS) regardless of treatment. Conversely, FFVHC control mice exhibited significantly elevated plasma ALT after 8 weeks on diet, which was exacerbated at 24 weeks relative to LF control and all GF groups. FF diets significantly increased (FFHC: P&lt;0.05; FFVHC: P&lt;0.01) plasma LBP after 24 weeks. Control mice fed FF diets exhibited severe steatosis, where FFVHC significantly increased NAS at 8 (P&lt;0.05) and 24 (P&lt;0.001) weeks relative to LF control and all GF groups. Microbiota profiling revealed no change in α‐diversity regardless of diet in control mice. β‐diversity analysis showed HF and FF diets, particularly FFVHC, rapidly shifted gut microbiota community membership after only 4 weeks, preceding disease onset and was further exacerbated over time. Liver RNA‐seq revealed FFVHC diet in control, but not GF, mice significantly enriched genes involved in the KEGG pathway, “antigen processing and presentation” (Bonferroni P&lt;0.001) relative to HF‐fed counterparts at 24 weeks.Taken together, FF diet‐induced shifts in gut microbes are both a prerequisite for and precede NAFLD/NASH disease onset, which is exacerbated by increased dietary cholesterol, driving liver inflammation. These data provide unique insights into how Western diet components impact host‐microbe interactions in complex liver diseases, which may aid in identifying novel therapeutic interventions.

Differential relationship between dietary fat and cholesterol on total mortality in Korean population cohorts.

Associations among dietary fat, cholesterol intake and total mortality remain controversial, and most available data cover Western populations. The aim of this study was to assess associations for dietary fat and cholesterol in relation to total mortality in Koreans. This study used data from three prospective Korean Genome and Epidemiology studies (conducted between June 2001 and December 2013). A total of 194,295 middle-aged and older Korean adults were included. Dietary fat intake was classified into quintiles. Dietary cholesterol intake was categorized into three groups based on cholesterol intake as follows: <200mg, 200-299mg and ≥300mg. A multivariable Cox frailty model with random effects was applied to calculate hazard ratios (HR) and 95% confidence intervals (CIs) after adjusting for confounders. We documented 3866 deaths across a mean (min-max) follow-up period of 8.15years (3-13years). Higher fat intake was associated with lower total mortality (Q5 vs. Q1, HR 0.82 [95% CI 0.69, 0.98]; p trend<0.01) after adjusting for age, sex, body mass index, alcohol, smoking, exercise and total calorie and protein (%) intake. Higher dietary cholesterol intake (≥300mg/day) was associated with a higher risk of total mortality (HR 1.19 [95% CI 1.04, 1.37]) than lower cholesterol intake (<200mg/day) in the multivariate model. In Koreans, high dietary fat intake is associated with a lower risk of total mortality, while dietary cholesterol intake above 300mg/day is associated with a higher risk of total mortality.

Dietary cholesterol and egg intake in relation to incident cardiovascular disease and all-cause and cause-specific mortality in postmenopausal women

The potential cardiovascular impact of dietary cholesterol intake has been actively debated for decades. We aimed to evaluate associations of dietary cholesterol and egg intakes with incident cardiovascular disease (CVD) and all-cause and cause-specific mortality. We included 96,831 US postmenopausal women aged 50-79 y without known CVD or cancer during baseline enrollment (1993-1998) of the Women's Health Initiative. Dietary information was collected using a validated FFQ. Incident CVD [i.e., ischemic heart disease (IHD) and stroke] and all-cause and cause-specific mortality were ascertained and adjudicated through February 2018. A total of 9808 incident CVD cases and 19,508 all-cause deaths occurred during a median follow-up of 17.8 y and 18.9 y, respectively. After multivariable adjustment for traditional risk factors and key dietary nutrients including dietary saturated fat, there were modest associations of dietary cholesterol intake with incident CVD (HRQ5versusQ1: 1.12; 95% CI: 1.03, 1.21; P-trend<0.001) and all-cause mortality (HRQ5versusQ1: 1.09; 95% CI: 1.02, 1.15; P-trend<0.001). Significant positive associations were also observed between dietary cholesterol and incident IHD (P-trend=0.007), incident ischemic stroke (P-trend=0.002), and CVD mortality (P-trend=0.002), whereas there was an inverse association for incident hemorrhagic stroke (P-trend=0.037) and no association for mortality from cancer, Alzheimer disease/dementia, respiratory diseases, or other causes (P-trend>0.05). Higher egg consumption was also associated with modestly higher risk of incident CVD (P-trend=0.004) and all-cause mortality (P-trend<0.001), with HRs of 1.14 (95% CI: 1.04, 1.25) and 1.14 (95% CI: 1.07, 1.22), respectively, when comparing ≥1 egg/d with <1 egg/wk. Both higher dietary cholesterol intake and higher egg consumption appeared to be associated with modestly elevated risk of incident CVD and all-cause mortality in US postmenopausal women.

Cholesterol as an Endogenous Ligand of ERRα Promotes ERRα-Mediated Cellular Proliferation and Metabolic Target Gene Expression in Breast Cancer Cells.

Breast cancer is the 2nd leading cause of cancer-related death among women. Increased risk of breast cancer has been associated with high dietary cholesterol intake. However, the underlying mechanisms are not known. The nuclear receptor, estrogen-related receptor alpha (ERRα), plays an important role in breast cancer cell metabolism, and its overexpression has been linked to poor survival. Here we identified cholesterol as an endogenous ligand of ERRα by purification from human pregnancy serum using a GST-ERRα affinity column and liquid chromatography-tandem mass spectrometry (LC-MS/MS). We show that cholesterol interacts with ERRα and induces its transcriptional activity in estrogen receptor positive (ER+) and triple negative breast cancer (TNBC) cells. In addition, we show that cholesterol enhances ERRα-PGC-1α interaction, induces ERRα expression itself, augments several metabolic target genes of ERRα, and increases cell proliferation and migration in both ER+ and TNBC cells. Furthermore, the stimulatory effect of cholesterol on metabolic gene expression, cell proliferation, and migration requires the ERRα pathway. These findings provide a mechanistic explanation for the increased breast cancer risk associated with high dietary cholesterol and possibly the pro-survival effect of statins in breast cancer patients, highlighting the clinical relevance of lowering cholesterol levels in breast cancer patients overexpressing ERRα.

Low Carbohydrate and Low-Fat Diets: What We Don't Know and Why we Should Know It.

In the 1940s, the diet-heart hypothesis proposed that high dietary saturated fat and cholesterol intake promoted coronary heart disease in “at-risk” individuals. This hypothesis prompted federal recommendations for a low-fat diet for “high risk” patients and as a preventive health measure for everyone except infants. The low carbohydrate diet, first used to treat type 1 diabetes, became a popular obesity therapy with the Atkins diet in the 1970s. Its predicted effectiveness was based largely on the hypothesis that insulin is the causa prima of weight gain and regain via hyperphagia and hypometabolism during and after weight reduction, and therefore reduced carbohydrate intake would promote and sustain weight loss. Based on literature reviews, there are insufficient randomized controlled inpatient studies examining the physiological significance of the mechanisms proposed to support one over the other. Outpatient studies can be confounded by poor diet compliance such that the quality and quantity of the energy intake cannot be ascertained. Many studies also fail to separate macronutrient quantity from quality. Overall, there is no conclusive evidence that the degree of weight loss or the duration of reduced weight maintenance are significantly affected by dietary macronutrient quantity beyond effects attributable to caloric intake. Further work is needed.

HC diet inhibited testosterone synthesis by activating endoplasmic reticulum stress in testicular Leydig cells.

Emerging epidemiological studies indicate that hypercholesterolaemia is a risk factor for testosterone deficiency. However, the underlying mechanism is unclear. Testicular Leydig cells are the primary source of testosterone in males. To identify the effect and mechanism of cholesterol overload on Leydig cell function, rats were fed with a HC (HC) diet to induce hypercholesterolaemia. During the 16‐week feeding period, serum testosterone levels were reduced in a time‐dependent manner in rats fed the HC diet. Accordingly, these steroidogenic enzymes within the Leydig cells, including steroidogenic acute regulatory protein (StAR), cholesterol side‐chain cleavage cytochrome P450 (P450scc) and 3β‐hydroxysteroid dehydrogenase (3β‐HSD), were down‐regulated. Notably, the HC‐fed rats showed evident endoplasmic reticulum (ER) stress in the testis, including a dilated ER as an evident pathological change in the Leydig cell ultrastructure, up‐regulated ER stress biomarker (binding immunoglobulin protein) levels and activation of the activating transcription factor 6 (ATF6)‐related unfolded protein response pathway. Further analysis showed that when 4‐phenyl butyric acid (4‐PBA) was used to block ER stress in HC‐fed rats for 8 weeks, the testosterone deficiency was significantly alleviated. Our findings suggested that high dietary cholesterol intake affected serum testosterone levels by down‐regulating steroidogenic enzymes and that activated ER stress might serve as the underlying mechanism.

Constraint-based explanation and repair of filter-based transformations

Data analysts often need to transform an existing dataset, such as with filtering, into a new dataset for downstream analysis. Even the most trivial of mistakes in this phase can introduce bias and lead to the formation of invalid conclusions. For example, consider a researcher identifying subjects for trials of a new statin drug. She might identify patients with a high dietary cholesterol intake as a population likely to benefit from the drug, however, selection of these individuals could bias the test population to those with a generally unhealthy lifestyle, thereby compromising the analysis. Reducing the potential for bias in the dataset transformation process can minimize the need to later engage in the tedious, time-consuming process of trying to eliminate bias while preserving the target dataset. We propose a novel interaction model for explain-and-repair data transformation systems, in which users inter-actively define constraints for transformation code and the resultant data. The system satisfies these constraints as far as possible, and provides an explanation for any problems encountered. We present an algorithm that yields filter-based transformation code satisfying user constraints. We implemented and evaluated a prototype of this architecture, E meril , using both synthetic and real-world datasets. Our approach finds solutions 34% more often and 77% more quickly than the previous state-of-the-art solution.

DIETARY CHOLESTEROL LOWERS RISK OF TYPE 2 DIABETES IN THE FRAMINGHAM OFFSPRING STUDY

Beginning in the 1960s, limiting dietary cholesterol (DC) was widely considered a strategy for protecting against cardiovascular disease (CVD) risk. Recently, the 2013 American College of Cardiology/American Heart Association Lifestyle Guidelines for the Reduction of Cardiovascular Disease concluded that the evidence was insufficient to support continued restriction of DC intake for prevention of CVD; the Dietary Guidelines Advisory Committee no longer considers DC to be a “nutrient of concern”. However, questions remain about whether DC is a risk factor for type 2 diabetes mellitus (T2DM). The objective of this study was to estimate the effects of DC alone and in combination with selected markers of a healthy diet (e.g. fruits &amp; vegetables, whole grains, fiber) on fasting glucose (FG) and risk of developing T2DM. Men and women without T2DM who were 35–64 years of age at the time of dietary assessment in the Framingham Offspring Study were included these analyses and followed for 20 years. Three‐day food records were collected at exams 3 and 5. Individuals were classified according to sex‐specific DC intake (low, moderate, and high intakes for men: &lt;200, 200–&lt;400, and ≥400 mg/day; for women: &lt;150, 150–&lt;350, and ≥350 mg/day). Longitudinal mixed models were used to estimate the adjusted mean fasting glucose (FG) at five follow‐up exams, 4 years apart. Cox proportional hazard's models were used to estimate the risk of developing T2DM; final models were adjusted for age, education, physical activity, cigarette smoking, alcohol intake, and baseline body mass index (BMI). At baseline, men consuming ≥400 mg of DC had lower mean FG than those consuming &lt;200 mg (FG: 93.8 vs 96.6, p‐trend: 0.0006); results were similar in women. There was no evidence that higher DC intake had an adverse effect on FG throughout all years of follow‐up. Among both men and women, longitudinal mixed models showed that those consuming the highest (vs. lowest) amounts of DC had the lowest FG levels at baseline (p&lt;0.0001) and lowest throughout the 20 years of follow‐up (p=0.0008). In addition, those subjects with high intakes of DC had a 22% lower risk of developing T2DM (HR: 0.78; 95% CI: 0.52–1.15) over time. To evaluate the combined effects of DC and other healthy diet patterns, we cross‐classified subjects according to their intake of both DC and the particular food serving as a marker of a healthy diet. The foods most strongly associated with a lower risk of T2DM and that modified the effects of DC were whole grains and fiber. Adults consuming ≥300 mg/day of DC and ≥0.5 servings/day of whole grains had a 38% lower risk of developing T2DM (95% CI: 0.41–0.93), while those consuming ≥300 mg/day of DC who had low whole intakes had only a 21% lower risk and those with lower DC intakes but higher intakes of whole grains had a 13% lower risk. These results suggest a positive synergistic effect between DC and whole grain consumption. Dietary fiber also modified the effects of DC on T2DM risk. Subjects consuming ≥300 mg/day of DC and ≥15 grams of dietary fiber had a 43% lower risk of T2DM (95% CI: 0.40–0.83) than those consuming less DC and less fiber. These results suggest that higher intakes of DC do not adversely affect fasting glucose levels or risk of T2DM and may even be beneficial when consumed in combination with a healthy diet.Support or Funding InformationNational Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. HHSN268201500001I) and a small grant from the American Egg Board ‐ Egg Nutrition Center.

High dietary cholesterol intake during lactation promotes development of fatty liver in offspring of mice.

We have previously demonstrated in mice that a maternal high fat diet during lactation enhances the susceptibility of offspring to obesity and fatty liver. A causative molecule, however, is yet to be identified. Therefore, we examined the role of cholesterol, the dietary intake of which increases with consumption of a high fat diet. Excessive cholesterol intake is involved in the development of fatty liver, which in turn becomes a risk factor for metabolic syndrome, which includes obesity, insulin resistance, and dyslipidemia. However, our knowledge of the influences on offspring of excessive maternal cholesterol intake alone during pregnancy and lactation is limited. We examined how excessive maternal cholesterol intake during lactation influences susceptibility of the offspring to metabolic syndrome in mice. High cholesterol intake promoted triacylglycerol accumulation in the liver of offspring (p < 0.05), and elevated expression of molecules involved in hepatic lipoprotein influx was identified as the underlying mechanism. These findings demonstrate that excessive maternal cholesterol intake during lactation enhances the susceptibility of the offspring to development of fatty liver.

Central Nervous System Demyelination and Remyelination is Independent from Systemic Cholesterol Level in Theiler's Murine Encephalomyelitis.

High dietary fat and/or cholesterol intake is a risk factor for multiple diseases and has been debated for multiple sclerosis. However, cholesterol biosynthesis is a key pathway during myelination and disturbances are described in demyelinating diseases. To address the possible interaction of dyslipidemia and demyelination, cholesterol biosynthesis gene expression, composition of the body's major lipid repositories and Paigen diet-induced, systemic hypercholesterolemia were examined in Theiler's murine encephalomyelitis (TME) using histology, immunohistochemistry, serum clinical chemistry, microarrays and high-performance thin layer chromatography. TME-virus (TMEV)-infected mice showed progressive loss of motor performance and demyelinating leukomyelitis. Gene expression associated with cholesterol biosynthesis was overall down-regulated in the spinal cord of TMEV-infected animals. Spinal cord levels of galactocerebroside and sphingomyelin were reduced on day 196 post TMEV infection. Paigen diet induced serum hypercholesterolemia and hepatic lipidosis. However, high dietary fat and cholesterol intake led to no significant differences in clinical course, inflammatory response, astrocytosis, and the amount of demyelination and remyelination in the spinal cord of TMEV-infected animals. The results suggest that down-regulation of cholesterol biosynthesis is a transcriptional marker for demyelination, quantitative loss of myelin-specific lipids, but not cholesterol occurs late in chronic demyelination, and serum hypercholesterolemia exhibited no significant effect on TMEV infection.

Ovariectomy in rats and high dietary cholesterol intake combine to decrease gene expression of molecular marker of VLDL synthesis

Ovariectomy in rats and high dietary cholesterol intake combine to decrease gene expression of molecular marker of VLDL synthesis

Cholesterol and egg intakes and the risk of type 2 diabetes: The Japan Public Health Center-based Prospective Study

Limited and inconsistent associations between cholesterol and egg consumption and type 2 diabetes risk have been observed in Western countries. In the present study, the association of dietary cholesterol and egg intakes with type 2 diabetes risk was examined prospectively. The study subjects comprised 27, 248 men and 36,218 women aged 45-75 years who participated in the second survey of the Japan Public Health Center-based Prospective Study and had no histories of type 2 diabetes or other serious diseases. Dietary cholesterol and egg intakes were estimated using a validated 147-item FFQ. The OR of self-reported, physician-diagnosed type 2 diabetes over 5 years were estimated using multiple logistic regression. A total of 1165 newly diagnosed cases of type 2 diabetes were self-reported. Although dietary cholesterol intake was not associated with type 2 diabetes risk in men, it was found to be associated with a 23 % lower odds of type 2 diabetes risk in women in the highest quartile of intake, albeit not statistically significant, compared with those in the lowest quartile (P trend= 0·08). Such risk reduction was somewhat greater among postmenopausal women; the multivariable-adjusted OR for the highest quartile of cholesterol intake compared with the lowest quartile was 0·68 (95 % CI 0·49, 0·94; P trend= 0·04). No association between egg intake and type 2 diabetes risk was found in either men or women. In conclusion, higher intake of cholesterol or eggs may not be associated with an increased risk of type 2 diabetes in Japanese populations. The observed association between decreased type 2 diabetes risk and higher dietary cholesterol intake in postmenopausal women warrants further investigation.

Lack of P2Y13 in mice fed a high cholesterol diet results in decreased hepatic cholesterol content, biliary lipid secretion and reverse cholesterol transport

BackgroundThe protective effect of HDL is mostly attributed to their metabolic function in reverse cholesterol transport (RCT), a process whereby excess cellular cholesterol is taken up from peripheral cells, processed in HDL particles, and later delivered to the liver for further metabolism and biliary secretion. Mechanistically, the purinergic P2Y13 ADP-receptor is involved in hepatic HDL endocytosis (i.e., uptake of both HDL protein + lipid moieties), which is considered an important step of RCT. Accordingly, chow-fed P2Y13 knockout (P2Y13-/-) mice exhibit lower hepatic HDL uptake, which translates into a decrease of hepatic free cholesterol content and biliary cholesterol and phospholipid secretion.FindingsThe aim of this study was to determine the effect of high cholesterol diet (HCD) in P2Y13-/- mice, in order to mimic high dietary cholesterol intake, which is a major cause of dyslipidemia in humans. As previously reported with chow-diet, HCD did not affect plasma lipid levels in P2Y13-/- compared with control mice but decreased hepatic free and esterified cholesterol content (p < 0.05, P2Y13-/- versus control). Interestingly, biliary lipid secretion and macrophages-to-feces RCT were more dramatically impaired in P2Y13-/- mice fed a HCD than chow-diet. HCD did not enhance atherosclerosis in P2Y13-/- compared with control mice.ConclusionThis study demonstrates that high dietary cholesterol intake accentuated the metabolic phenotype of P2Y13-/- mice, with impaired hepatobiliary RCT. Although other animal models might be required to further evaluate the role of P2Y13 receptor in atherosclerosis, P2Y13 appears a promising target for therapeutic intervention aiming to stimulate RCT, particularly in individuals with lipid-rich diet.

Diphenyl Diselenide Prevents Cortico-cerebral Mitochondrial Dysfunction and Oxidative Stress Induced by Hypercholesterolemia in LDL Receptor Knockout Mice

Recent studies have indicated a causal link between high dietary cholesterol intake and brain oxidative stress. In particular, we have previously shown a positive correlation between elevated plasma cholesterol levels, cortico-cerebral oxidative stress and mitochondrial dysfunction in low density lipoprotein receptor knockout (LDLr(-/-)) mice, a mouse model of familial hypercholesterolemia. Here we show that the organoselenium compound diphenyl diselenide (PhSe)2 (1 mg/kg; o.g., once a day for 30 days) significantly blunted the cortico-cerebral oxidative stress and mitochondrial dysfunction induced by a hypercholesterolemic diet in LDLr(-/-) mice. (PhSe)2 effectively prevented the inhibition of complex I and II activities, significantly increased the reduced glutathione (GSH) content and reduced lipoperoxidation in the cerebral cortex of hypercholesterolemic LDLr(-/-) mice. Overall, (PhSe)2 may be a promising molecule to protect against hypercholesterolemia-induced effects on the central nervous system, in addition to its already demonstrated antiatherogenic effects.