Thyroid-stimulating hormone (TSH) is a pituitary hormone that stimulates the thyroid gland to produce and release thyroid hormones, primarily thyroxine and triiodothyronine. These hormones are key players in body-brain communication, influencing various physiological processes, including the regulation of metabolism (both peripheral and central effects), feedback mechanisms, and lipid metabolism. Recently, the increasing incidence of abnormal lipid metabolism has highlighted the link between thyroid function and lipid metabolism. Evidence suggests that TSH can affect all bodily systems through body-brain communication, playing a crucial role in growth, development, and the regulation of various physiological systems. Lipids serve dual purposes: they are involved in energy storage and metabolism, and they act as vital signaling molecules in numerous cellular activities, maintaining overall human health or contributing to various diseases. This article reviews the role of TSH in regulating lipid metabolism via body-brain crosstalk, focusing on its implications for common lipid metabolism disorders such as obesity, atherosclerosis, nonalcoholic fatty liver disease, neuropsychiatric disorders (including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and depression), and cerebrovascular disorders such as stroke.

The incidence of dementia is steadily increasing worldwide. The risk factors for dementia are diverse, and include genetic background, environmental factors, sex differences, and vascular abnormalities. Among the subtypes of dementia, diabetes-related dementia is emerging as a complex type of dementia related to metabolic imbalance, due to the increase in the number of patients with metabolic syndrome and dementia worldwide. Thyroid hormones are considered metabolic regulatory hormones and affect various diseases, such as liver failure, obesity, and dementia. Thyroid dysregulation affects various cellular mechanisms and is linked to multiple disease pathologies. In particular, hypothyroidism is considered a critical cause for various neurological problems-such as metabolic disease, depressive symptoms, and dementia-in the central nervous system. Recent studies have demonstrated the relationship between hypothyroidism and brain insulin resistance and dyslipidemia, leading to diabetes-related dementia. Therefore, we reviewed the relationship between hypothyroidism and diabetes-related dementia, with a focus on major features of diabetes-related dementia such as insulin resistance, neuronal dysfunction, and dyslipidemia.

Alzheimer' disease is a neurodegenerative disorder characterized by the misfolding and aggregation of amyloid β (Aβ). This process is influenced through supply of cholesterol via apolipoproteins to neurons. In the present study, we used the transgenic Caenorhabditis elegans strain CL2006, which expresses Aβ1-42 under control of a muscle-specific promoter, to test the effects of the apolipoprotein B homologue vitellogenin-6 on paralysis. Knockdown of vitellogenin-6 using RNA-interference (RNAi) recently was shown to significantly reduce cholesterol absorption in C. elegans, and both, RNAi for vitellogenin-6 or lowering the cholesterol concentration in the medium was associated with reduced Aβ-aggregation and paralysis in the nematodes. The effects of both interventions are mediated through the inhibition of the steroidal-signaling pathway since knockdown of its key factors DAF-9 or DAF-12 reduced paralysis independent of the cholesterol concentration and without additive effects by vitellogenin-6 RNAi. Double-RNAi for daf-12 and the downstream target of insulin-signaling, the foxo transcription factor daf-16, revealed that the paralysis-triggering effects of daf-16 RNAi were dominant over the preventive effects of daf-12 RNAi. Identical observations were made when the transcriptional co-activators of DAF-16, ftt-2 or par-5 were knocked down instead of daf-16. In conclusion, interactions between the steroidal and insulin-signaling pathways were identified in Aβ1-42 expressing CL2006, where cholesterol deprivation inhibits steroidal-signaling and thereby activates DAF-16-signaling. Those effects were associated with a reduced Alzheimer phenotype in the nematodes, i.e. reduced protein aggregation and paralysis.

Obesity is associated with insulin resistance, development of diabetes, and coronary heart disease. There is limited information on the contribution of previous obesity on the risk of coronary heart disease. We aimed to examine the effect of previous history of obesity on the occurrence of coronary heart disease in patients with diabetes.

We carried out a retrospective chart analysis of 315 type 2 diabetic patients without obesity and without atherosclerotic cardiovascular events at their initial hospital visit (men/women 236/79; mean ± standard deviation; age 53.1 ± 6.6 years; maximal body mass index before enrollment (MAXBMI) 26.6 ± 3.4 kg/m2; decrease of the BMI at enrollment from MAXBMI (deltaBMI) 4.23 ± 2.62 kg/m2) to investigate the association of previous obesity (MAXBMI larger than 30 kg/m2) with the long-term incidence of cardiovascular events. Of 315 patients, forty-eight were previously obese.

After median follow-up of 13.9 years, 48 patients developed coronary heart disease. The Kaplan-Meier analysis exhibited that coronary heart disease occurred more frequently in previously obese patients than in subjects in the reference category (22 kg/m2 < or = MAXBMI < 25 kg/m2) and that the effect lasted proportionally over follow-up periods. Multivariate Cox regression models showed that hazard ratios and corresponding 95% confidence intervals of coronary heart disease for patients with previous obesity compared with subjects in the reference category were 2.52 and 1.15 to 5.50 (p value = 0.020) after adjustment for age, sex, smoking status, systolic blood pressure, total cholesterol and HDL cholesterol. In this cohort, deltaBMI strongly correlated with MAXBMI and also behaved as a risk factor. The hazard ratios and 95% confidence intervals by the increment of one standard deviation of deltaBMI after adjustment for age, sex, smoking status, systolic blood pressure, total cholesterol and HDL cholesterol were 1.38 and 1.08 to 1.79 (p value = 0.013).

Previous obesity and/or large body weight loss before admission might act as an increased risk for coronary heart disease.

Whether cholesterol is implicated in the pathogenesis of Alzheimer's disease (AD) is still controversial. Several studies that explored the association between lipids and/or lipid-lowering treatment and AD indicate a harmful effect of dyslipidemia on AD risk. The findings are supported by genetic linkage and association studies that have clearly identified several genes involved in cholesterol metabolism or transport as AD susceptibility genes, including apolipoprotein E (APOE), apolipoprotein J (APOJ, CLU), ATP-binding cassette subfamily A member 7(ABCA7), and sortilin-related receptor (SORL1). Functional cell biology studies further support a critical involvement of lipid raft cholesterol in the modulation of Aβ precursor protein processing by β-secretase and γ-secretase resulting in altered Aβ production. However, conflicting evidence comes from epidemiological studies showing no or controversial association between dyslipidemia and AD risk, randomized clinical trials observing no beneficial effect of statin therapy, and cell biology studies suggesting that there is little exchange between circulating and brain cholesterol, that increased membrane cholesterol level is protective by inhibiting loss of membrane integrity through amyloid cytotoxicity, and that cellular cholesterol inhibits colocalization of β-secretase 1 and Aβ precursor protein in nonraft membrane domains, thereby increasing generation of plasmin, an Aβ-degrading enzyme. The aim of this article is to provide a comprehensive review of the findings of epidemiological, genetic, and cell biology studies aiming to elucidate the role of cholesterol in the pathogenesis of AD.

The role of cholesterol in the etiology of Alzheimer's disease (AD) is still controversial. Some studies exploring the association between lipids and/or lipid lowering treatment and AD indicate a harmful effect of dyslipidemia and a beneficial effect of statin therapy on AD risk. The findings are supported by genetic linkage and association studies that have clearly identified several genes involved in cholesterol metabolism or transport as AD susceptibility genes, including apolipoprotein E, apolipoprotein J, and the sortilin-related receptor. Functional cell biology studies support a critical involvement of lipid raft cholesterol in the modulation of amyloid-β protein precursor (AβPP) processing by β- and γ-secretase resulting in altered amyloid-β production. Contradictory evidence comes from epidemiological studies showing no or controversial association between dyslipidemia and AD risk. Additionally, cell biology studies suggest that there is little exchange between circulating and brain cholesterol, that increased membrane cholesterol is protective by inhibiting loss of membrane integrity through amyloid cytotoxicity, and that cellular cholesterol inhibits co-localization of BACE1 and AβPP in non-raft membrane domains, thereby increasing generation of plasmin, an amyloid-β-degrading enzyme. The aim of this review is to summarize the findings of epidemiological and cell biological studies to elucidate the role of cholesterol in AD etiology.

Intake of dairy fat has long been considered as a risk factor for CVD. Pasture and dietary lipid supplementation have been reported to be reliable strategies in ruminant nutrition, in order to increase the content of α-linolenic acid (ALA), conjugated linoleic acid (CLA) and vaccenic acid (VA), and decrease SFA in milk fat. In the present study, we aimed at verifying whether consumption of a sheep cheese, naturally enriched in ALA, CLA and VA, would modify the plasma lipid and endocannabinoid profiles in mildly hypercholesterolaemic subjects. A total of forty-two adult volunteers (nineteen males and twenty-three females) with diagnosed mildly hypercholesterolaemia (total cholesterol 5·68-7·49 mmol/l) were randomly assigned to eat 90 g/d of a control or enriched cheese for 3 weeks, with a cross-over after 3 weeks of washout. Plasma lipids, endocannabinoids, adipokines and inflammatory markers were measured. The intake of enriched cheese significantly increased the plasma concentrations of CLA, VA, the n-3 fatty acids ALA and EPA, and more remarkably decreased that of the endocannabinoid anandamide. LDL-cholesterol decreased significantly (7%). No changes were detected in the levels of inflammatory markers; however, a significant correlation was found between the plasma levels of anandamide and leptin. The control cheese modified none of the parameters measured. The results obtained do not support the view that intake of dairy fat is detrimental to hypercholesterolaemic subjects. Indeed, they show that a naturally enriched cheese possesses beneficial properties, since it ameliorates the plasma lipid profile, and more remarkably reduces endocannabinoid biosynthesis.

To analyze the risk of coronary heart disease in patients with type 2 diabetes mellitus (T2DM) receiving standard medical treatment.

We performed a retrospective chart analysis of 269 middle-aged patients (age 45-64 years, mean age, 53.9 ± 5.5 years) with T2DM and without atherosclerotic cardiovascular events who underwent typing to determine their apolipoprotein E (apoE) isoforms. The apoE isoforms were determined using isoelectric focusing, followed by immunoblotting. We retrospectively evaluated the charts of the 269 patients, recorded between their first visit to the hospital (the study's start point, between 1987 and 1992) and the occurrence of an atherosclerotic cardiovascular event (the study's endpoint) or January 2004, whichever came first. The age-adjusted mean values and the prevalences of covariates were calculated to compare the laboratory data among the apoE phenotypes. To investigate the association of risk factors with the incidence of coronary heart disease during the follow-up period, monovariate and multivariate Cox regression models were used.

At enrollment, the mean serum low density lipoprotein (LDL) cholesterol levels were lowest (2.92 ± 0.89 mmol/L) among the subjects with apoE2 (apoE2/2 or apoE2/3) and highest (3.52 ± 0.77 mmol/L) among the subjects with apoE4 (apoE3/4 or apoE4/4). No significant differences in mean age or the percentage of smokers were observed among the three groups. Furthermore, no significant differences were observed in the systolic and diastolic blood pressures, body mass index, HbA1c level or serum triglyceride levels among the three groups. There were 47 cases of coronary heart disease over 3285 person-years of follow-up. An age-adjusted multivariate Cox proportional model identified diabetic retinopathy (hazard ratio, 2.38, 95% CI: 1.28-4.43, P = 0.006), a high systolic blood pressure (hazard ratio, 1.04, 95% CI: 1.02-1.06, P < 0.001) and high HbA1c values (hazard ratio, 1.19, 95% CI: 1.02-1.38, P = 0.0029), but not the LDL cholesterol value at enrollment (hazard ratio, 1.01, 95% CI: 0.97-1.05, P = 0.77) nor the specific apoE isoform, as significant predictors of coronary heart disease.

Under standard medical treatment of diabetes, including the control of LDL cholesterol levels, the apoE4 isoform was not associated with coronary heart disease among T2DM patients.

Epidemiological, animal, and cellular studies suggest that abnormalities in cholesterol metabolism are important in the pathogenesis of Alzheimer's disease (AD), potentially by increasing amyloid-beta (Abeta) peptide levels. Accumulation of Abeta in the brain is suggested to play a key role in the neurodegenerative processes by triggering the hyperphosphorylation of tau and the neuronal death that develop in the course of AD. However, the mechanisms by which cholesterol increases Abeta levels are still ill-defined. Previous and ongoing work from our laboratory indicates that hypercholesterolemia leads to the increased neuronal content of cholesterol and increased levels and processing of the amyloid-beta protein precursor (AbetaPP). We also have found that the oxidized cholesterol metabolite, 27-hydroxycholesterol, increases Abeta levels in both organotypic hippocampal slices and in neuronal preparations cultured from adult rabbits. This cholesterol metabolite is predominantly formed in the circulation and, in contrast to cholesterol, has the ability to cross into the brain. These results may indicate that 27-hydroxycholesterol is the link between circulating cholesterol and AD-like pathology in the brain. We also have found pathological hallmarks in the skeletal muscle of cholesterol-fed rabbits that are suggestive of inclusion body myositis, a disease that shares some pathological similarities with AD.

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia and affects up to 15 million people worldwide. Although no single cause of AD has been identified, recent research has suggested that several pathogenetic factors influence risk and expression. A growing amount of evidence underscores a mechanistic link between cholesterol metabolism in the brain and the formation of amyloid plaques. Excess brain cholesterol has been associated with increased formation and deposition of amyloid-beta peptide from amyloid precursor protein. Cholesterol-lowering statins have become a focus of research in AD. Genetic polymorphisms associated with pivotal points in cholesterol metabolism in brain tissues may contribute to the risk and pathogenesis of AD. In this review, we summarise current knowledge of the role of cholesterol metabolism in the pathogenesis of AD and examine the potential of statins in the prevention and treatment of AD.

The aim of this study was to investigate the effect of apolipoprotein (apo)E4 allele on plasma LDL cholesterol response to calorie-restricted diet therapy in type 2 diabetic patients.

Twenty-four diabetic patients with the apoE3/3 genotype and 11 diabetic patients with the apoE4/3 genotype were recruited. Participants were hospitalized for calorie-restricted diet therapy (25.0 kcal. kg body wt(-1). day(-1)) for 14 days. Body weight, fasting plasma glucose (FPG) levels, and plasma lipid levels on hospital days 1 and 14 were compared between the two apoE genotype groups.

There were no significant differences in baseline FPG levels, HbA(1c) levels, BMI, and plasma levels of total cholesterol, triglyceride, and HDL cholesterol between the two apoE genotype groups, but baseline plasma levels of LDL cholesterol were significantly higher in the apoE4/3 group than in the apoE3/3 group. Body weight decreased slightly and FPG levels decreased significantly after diet therapy in both apoE genotype groups. In the apoE3/3 group, only plasma levels of triglyceride decreased significantly after diet therapy, whereas in the apoE4/3 group, plasma levels of triglyceride, total cholesterol, and LDL cholesterol decreased significantly after diet therapy. The decrease (percentage of change) in total cholesterol (-16.3 vs. -6.6%) and LDL cholesterol (-15.6 vs. -0.7%) after diet therapy was significantly greater in the apoE4/3 group than in the apoE3/3 group.

Calorie-restricted diet therapy is more effective in reducing plasma LDL cholesterol in type 2 diabetic patients with the apoE4 allele.

Hyperlipidaemia is a major predisposing factor to atherosclerosis in patients with type 2 diabetes. Apolipoprotein (apo) E polymorphism influences lipoprotein metabolism, and the present study was undertaken to explore the relation, in type 2 diabetics, between apo E genotype and the plasma lipid response to dietary therapy.

The subjects were 104 patients with type 2 diabetes and hyperlipidaemia, and the difference, due to apo E genotype, in dietary response was followed for 4-6 weeks. The caloric intake was maintained in the range 20-25 kcal/kg, and the medications for diabetes were not changed during the follow-up period.

Plasma total cholesterol (TC) and triglyceride (TG) levels were significantly lowered by the dietary treatment in patients with apo E genotypes of epsilon3/3, epsilon2/3 and epsilon3/4; however, the lipid levels in patients with epsilon2/4 did not respond to the diet.

apo E genotype should be taken into consideration in the treatment of hyperlipidaemia in diabetic patients.

To evaluate the influence of variation in the genes for apolipoprotein E (APOE; epsilon2, epsilon3, epsilon4) and cholesterol-7alpha hydroxylase (CYP-7A1; -204A-->C) on plasma lipid level changes.

131 males for whom dietary composition markedly changed and total cholesterol decreased (from 6.21 +/- 1.31 mmol/L in 1988 - 5.43 +/- 1.06 mmol/L in 1996) over an 8 yr follow-up study. Polymorphisms were investigated using PCR.

APOE genotype influenced plasma total and LDL cholesterol, with carriers of the epsilon4 having the highest and epsilon2 carriers the lowest levels, this reached borderline significance for cholesterol in 1988 (p = 0.06) and strongly affected the 1996 levels of LDL cholesterol (p = 0.008). However, APOE did not influence the change in these measures over time. In contrast, the CYP-7A1 -204A-->C polymorphism did not affect lipid measures per se but was strongly associated with a decrease in plasma total cholesterol [AA -0.38 (+/- 0.20) mmol/L, AC -0.65 +/- (0.08), CC -1.33 (+/- 0.3) mmol/L, p = 0.01] over the 8 yr time period.

Variation in the CYP-7A1 gene may play an important role in an individual's sensitivity to dietary composition.

Apolipoprotein E allele 4 (apo epsilon4) and smoking each have been associated with an unfavorable lipid profile. We used data collected on 1,472 subjects in the National Heart, Lung, and Blood Institute Family Heart Study to assess whether smoking interacts with apo epsilon4 to influence the levels of plasma lipids. We dichotomized smoking and apo epsilon4 and used analysis of covariance to estimate the means of lipids. Smokers had lower body mass index, were younger, and consumed less fruits and vegetables. Among individuals without apo epsilon4, comparing nonsmokers with smokers, mean low density lipoprotein cholesterol (LDL) was 129.3 and 134.4 mg/dL, respectively, for women and 126.1 and 127.6 mg/dL, respectively, for men. Among subjects with an apo epsilon4 allele, corresponding means were 132.0, and 152.9 mg/dL, respectively, for women and 131.3 and 137.3 mg/dL, respectively, for men (Pfor interaction <0.001 for women and 0.11 for men). A similar interaction was observed for total cholesterol among women (P = 0.02). This study shows a statistically significant effect modification of the relation of apo epsilon4 to LDL and total cholesterol by smoking among women. Smoking may enhance genetic susceptibility to an unfavorable lipid profile among subjects with apo epsilon4.

Variation at the apolipoprotein E (APOE) gene locus has demonstrated a consistent impact on lipoprotein levels. APOE typing was performed for 488 healthy, caucasian, premenopausal women participating in the Women's Healthy Lifestyle Project (WHLP) aimed at reducing total fat, saturated fat and cholesterol intake and promoting physical activity. Women in both the intervention and control groups were included in the trial. The purpose of the present study was to determine whether the magnitude of the changes in total cholesterol (Tc), low density lipoprotein cholesterol (LDLc) and high density lipoprotein cholesterol (HDLc) due to the dietary intervention were dependent on the variation in APOE. Weight, body mass index (BMI), and lipoprotein levels were measured at baseline and at a 6 month follow-up. ANOVA was used to determine whether the change in Tc and LDLc was dependent on dietary intervention and variation at APOE levels. The levels of Tc and LDLc were higher in women with the APOE*4 genotype. There were no statistically significant effects of APOE genotype and changes in Tc and LDLc (P > 0.1). Adjusted Tc and LDLc changes were comparable in the 3 APOE subgroups (Tc = -14.3, -12.9 and -11.7 mg/dl; LDLc = -12.1, -10.7 and -10.7 mg/dl, respectively as above). In conclusion, the genetic (APOE) background of premenopausal women in this study did not have a significant effect on their response to dietary intervention.

Polymorphisms in the apolipoprotein E (apoE) phenotype (especially E4) are associated with increased cardiovascular risk and particularly with increased concentrations of LDL cholesterol. Little is known, however, about whether alterations in LDL size are associated with the apoE4 phenotype. LDL size was determined by gradient gel electrophoresis, and apoE phenotype was determined by isoelectric focus in 337 nondiabetic subjects from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular risk factors in Mexican Americans and non-Hispanic whites. ApoE4 was associated not only with increases in LDL cholesterol concentrations but also with decreased LDL size. After adjustment for age, sex, body mass index, waist-to-hip ratio, triglyceride, HDL cholesterol, fasting insulin, and diabetic status, the apoE phenotype remained significantly related to LDL size (A) in both men (apoE23, 260.0; apoE33; 256.3; and apoE34, 252.6; P = .01) and women (apoE23, 261.7; apoE33, 257.9; and apoE34, 256.7, P = .045). Variations in apoE phenotype are associated not only with changes in the absolute concentration of LDL cholesterol but also with changes in its composition. These changes are only partly explained by associations of apoE with insulin, triglyceride, and HDL cholesterol.