Increased Serum Cholesterol Levels Research Articles

Effects of PFAS on human liver transporters: implications for health outcomes.

Per- and polyfluoroalkyl substances (PFAS) have become internationally recognized over the past three decades as persistent organic pollutants used in the production of various consumer and industrial goods. Research efforts continue to gauge the risk that historically used, and newly produced, PFAS may cause to human health. Numerous studies report toxic effects of PFAS on the human liver as well as increased serum cholesterol levels in adults. A major concern with PFAS, also dubbed "forever chemicals", is that they accumulate in liver and kidney and persist in serum. The mechanisms responsible for their disposition and excretion in humans are poorly understood. A better understanding of the interaction of PFAS with liver transporters, as it pertains to the disposition of PFAS and other xenobiotics, could provide mechanistic insight into human health effects and guide efforts toward risk assessment of compounds in development. This review summarizes the current state of the literature on the emerging relationships (e.g., substrates, inhibitors, modulators of gene expression) between PFAS and specific hepatic transporters. The adaptive and toxicological responses of hepatocytes to PFAS that reveal linkages to pathologies and epidemiological findings are highlighted. The evidence suggests that our understanding of the molecular landscape of PFAS must improve to determine their impact on the expression and function of hepatocyte transporters that play a key role in PFAS or other xenobiotic disposition. From here, we can assess what role these changes may have in documented human health outcomes.

Osteocytes/Osteoblasts Produce SAA3 to Regulate Hepatic Metabolism of Cholesterol.

Hypercholesterolaemia is a systemic metabolic disease, but the role of organs other than liver in cholesterol metabolism is unappreciated. The phenotypic characterization of the Tsc1Dmp1 mice reveal that genetic depletion of tuberous sclerosis complex 1 (TSC1) in osteocytes/osteoblasts (Dmp1-Cre) triggers progressive increase in serum cholesterol level. The resulting cholesterol metabolic dysregulation is shown to be associated with upregulation and elevation of serum amyloid A3 (SAA3), a lipid metabolism related factor, in the bone and serum respectively. SAA3, elicited from the bone, bound to toll-like receptor 4 (TLR4) on hepatocytes to phosphorylate c-Jun, and caused impeded conversion of cholesterol to bile acids via suppression on cholesterol 7 α-hydroxylase (Cyp7a1) expression. Ablation of Saa3 in Tsc1Dmp1 mice prevented the CYP7A1 reduction in liver and cholesterol elevation in serum. These results expand the understanding of bone function and hepatic regulation of cholesterol metabolism and uncover a potential therapeutic use of pharmacological modulation of SAA3 in hypercholesterolaemia.

Association between dyslipidemia and rotator cuff tear – A study

Introduction and Aim: Rotator cuff diseases are the most common soft tissue injuries in the upper extremity with incidence ranging from 5% to 39%. The causes of rotator cuff tendon ruptures are multifactorial. Both extrinsic and intrinsic factors affect the degeneration of rotator cuff muscles. Few animal studies have shown detrimental effects on tendons in the presence of high lipid levels. The goal of the current investigation was to determine whether abnormal blood lipid levels and rotator cuff tears are related. Materials and Methods: This cross-sectional study was carried out in a hospital setting at the AJ Institute of Medical Sciences and Research Centre in Mangalore over a 24-month period. The sample size obtained was 93 with the convenience sampling technique. The research involved clinical examination and routine blood investigations, fasting lipid profile and radiological examination. Following all the data collection, an association was assessed between fasting lipid values and rotator cuff tear using statistical analysis. Results: Sixty-eight patients had an increased serum cholesterol level, which was shown to have a significant association with rotator cuff tear (chi square = 12.102 and p = 0.007). 52 patients suffering from rotator cuff tear had a low level of HDL, which was shown to have a statistically significant association (chi square = 13.098 and p = 0.042). 55 patients with rotator cuff tears had high LDL levels, which were shown to have a statistically significant association, (chi square = 9.487 and p = 0.023). 75 patients with rotator cuff tears had high triglyceride levels, which were shown to have a statistically significant association chi square = 8.044 and p = 0.044. Conclusion: Our research revealed a statistically significant correlation between rotator cuff injuries and elevated serum cholesterol, triglycerides, LDL levels, and low HDL levels.

Dietary cholesterol intake is not associated with the development of chronic kidney disease: Results from two Korean cohort studies

Background and aimsAlthough dyslipidemia is a major risk factor for chronic kidney disease (CKD), the relationship between dietary cholesterol and CKD remains unknown. We investigated the association between cholesterol intake and CKD risk. Methods and resultsThe Korea National Health and Nutrition Examination Survey (KNHANES) 2019–2021 (n = 13,769) and the Korean Genome and Epidemiology Study (KoGES) (n = 9225) data were used for this study. Cholesterol intake was assessed using a 24-h recall food frequency questionnaire, and participants were categorized into three groups (T1, T2, and T3) based on cholesterol intake. Primary outcomes were prevalence and incidence of CKD. Higher cholesterol intake was modestly associated with increased serum levels of total, low-density lipoprotein, and high-density lipoprotein cholesterol in the KNHANES. However, we found no significant association between cholesterol intake and CKD prevalence in the KNHANES, regardless of a history of hypercholesterolemia. In the KoGES, during a median follow-up of 11.4 years, cholesterol intake was not associated with incident CKD in participants without hypercholesterolemia (hazard ratio [HR] per 10 mg increase, 1.00; 95 % confidence interval [CI], 0.99–1.01) and in those with hypercholesterolemia (HR, 1.01; 95 % CI, 0.98–1.04). Egg consumption also showed no significant association with the risk of incident CKD. Additionally, cholesterol intake had no significant interaction on the relationships between serum cholesterol levels and incident CKD. ConclusionAlthough cholesterol intake was associated with increased serum cholesterol levels, it was not associated with CKD prevalence and incidence. Our findings suggest that reducing cholesterol intake alone may not be sufficient to prevent CKD.

High-salt diet induces dyslipidemia through the SREBP2/PCSK9 pathway in dahl salt-sensitive rats

A high-salt diet is known to increase serum cholesterol levels; however, the underlying mechanism of salt-induced dyslipidemia in patients with salt-sensitivity remains poorly understood. We aimed to investigate whether high-salt diet (HSD) can induce dyslipidemia and elucidate the underlying mechanism of salt-induced dyslipidemia in Dahl salt-sensitive (SS) rats. Metabolomic and biochemical analyses revealed that the consumption of an HSD (8 % NaCl) significantly increased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in SS rats. The enzyme-linked immunosorbent assay demonstrated an increase in circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, accompanied by a decrease in hepatic low-density lipoprotein receptor (LDLR) levels due to HSD consumption. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis revealed that HSD consumption activated sterol regulatory element-binding protein-2 (SREBP2) expression in the liver and kidney, resulting in upregulation of PCSK9 at the transcriptional level in the liver and at the translational level in the kidney, ultimately increasing circulating PCSK9 levels. The combined effects of HSD on the liver and kidney contributed to the development of hypercholesterolemia. Furthermore, an in vitro assay confirmed that high-salt exposure led to an increase in the protein expression of SREBP2 and PCSK9 secretion, thereby reducing low-density lipoprotein (LDL) uptake. This study, for the first time, shows that an HSD induces dyslipidemia through activation of the SREBP2/PCSK9 pathway, providing new insights into the prevention and treatment of dyslipidemia in patients with salt sensitivity.

Cholesterol Efflux Drives the Generation of Immunosuppressive Macrophages to Promote the Progression of Human Hepatocellular Carcinoma.

Cholesterol is often enriched in tumor microenvironment (TME); however, its impact on disease progression varies in different tissues and cells. Monocytes/macrophages (Mφ) are major components and regulators of the TME and play pivotal roles in tumor progression and therapeutic responses. We aimed to investigate the profile, effects, and regulatory mechanisms of Mφ cholesterol metabolism in the context of human hepatocellular carcinoma (HCC). Here, we found that patients with high serum levels of cholesterol had shorter survival times and lower response rates to anti-PD-1 treatment. However, the cholesterol content in tumor-infiltrating monocytes/Mφ was significantly lower than that in their counterparts in paired nontumor tissues. The expression of the cholesterol efflux transporter, ABCA1, was upregulated in tumor monocytes/Mφ, and ABCA1 upregulation positively associated with decreased cellular cholesterol content and increased serum cholesterol levels. Mechanistically, autocrine cytokines from tumor-treated monocytes increased LXRα and ABCA1 expression, which led to the generation of immature and immunosuppressive Mφ. Although exogenous cholesterol alone had little direct effect on Mφ, it did act synergistically with tumor-derived factors to promote ABCA1 expression in Mφ with more immunosuppressive features. Moreover, high numbers of ABCA1+ Mφ in HCC tumors associated with reduced CD8+ T-cell infiltration and predicted poor clinical outcome for patients. Our results revealed that dysregulated cholesterol homeostasis, due to the collaborative effects of tumors and exogenous cholesterol, drives the generation of immunosuppressive Mφ. The selective modulation of cholesterol metabolism in Mφ may represent a novel strategy for cancer treatment.

Blood group in relation to oral Fordyce's granules and serum cholesterol level.

The ABO and Rh systems are the most commonly used blood-group systems used to classify blood group globally. A number of studies have shown that ABO blood groups may be associated with an increased serum cholesterol levels which in turn may be related to the presence of oral Fordyce spots or granules. Oral Fordyce's granules are ectopic sebaceous glands within the oral cavity and are visible through epithelium. The aim of this study was to assess the relationship between ABO and Rhesus blood groups and the presence of oral Fordyce's granules and serum cholesterols level by gender. Following ethical approval and informed consent, 124 subjects were recruited into this cross-sectional study. Clinical oral examination assessed the number of Fordyce's granules and blood samples were collected to determine the serum cholesterol and ABO/Rh blood-group systems of individual subjects. Blood group AB+ showed the highest mean of oral Fordyce's granules number and serum cholesterol level but this was not statistically significant compared to other blood groups. Female subjects in this study who were AB+ were had significantly higher serum cholesterol levels than males. This study indicates an association between ABO blood group, serum cholesterol level and mean number of oral Fordyce's granules. A larger sample size in a future study is required to ascertain whether number of Fordyce's granules is an important measure of serum cholesterol, but the study does show that for AB+ individuals, females may have higher serum cholesterol than males.

An Investigation of Insulin Resistance and Cachexia Relation in Patients with Metastatic Gastrointestinal Malignancies

Background: Insulin resistance has been suggested as one of the known metabolic disorders during cachexia. This study hypothesized that cachexia in cancer patients might be related to insulin resistance as early as cachexia development.
 Methods: This study was performed on 46 patients with metastatic gastrointestinal cancer. Anthropometric characteristics and biochemical markers were assessed at baseline, second and third month. Insulin resistance was assessed using the homeostasis model assessment-estimated insulin resistance (HOMA IR) method. SFQ-36 questions were used to assess the patients' quality of life at baseline, second and third months.
 Results: Anthropometric characteristic was significantly associated between pre-cachectic and non-pre-cachectic patients in third month. Cholesterol (P-value = 0.93), albumin (P-value: 0.82), and serum creatinine (P-value = 0.88) in pre-cachectic patients decreased over three months. There was an increasing trend of insulin resistance between pre-cachectic and non-pre-cachectic patients in third month. Cholesterol had an upward trend with a significant relation in cachectic patients [(P-value = 0.00), (P-value = 0.03), (P-value = 0.01)]. We detected a decreasing trend of insulin resistance between cachectic and non-cachectic patients from second to third month (P-value = 0.04). SFQ evaluation had no significant relation with cachectic status.
 Conclusion: Previous studies showed that the use of NSAIDs, progesterone’s, corticosteroids, COX-2 inhibitors, anabolic agents and drugs targeting inflammatory cytokines may be beneficial for improving of symptoms of cachexia. Significant relation between anthropometric variables with pre-cachexia and cachectic conditions was concluded. Patients' outcome and its relation with insulin resistance demonstrated a significant relation between the cachectic and non-cachectic patients in the third month. We also detected the increased serum cholesterol level in cachectic patients, moreover, higher cholesterol levels in expired cachectic patients than in the living.

Effect of Lindane (δ- isomer) on Serum cholesterol and Liver enzyme markers in mice (Mus musculus)

In the present study, we investigate the serum cholesterol level and the liver enzymes (alkaline phosphatase, alanine transaminase, and aspartate aminotransferase) in mice. Lindane (δ- isomer), 100mg/kg body weight, injected subcutaneously for 30 days. Our present study found that after 30 days of lindane administration, after sacrificing the mice, a significant increase in serum cholesterol levels observed. Alkaline phosphatase levels significantly decreased, whereas the alanine transaminase and aspartate aminotransferase levels significantly increased.

The association between the skeletal muscle state, lipid metabolism disorders and the development of insulin resistance in children with type 1 diabetes mellitus

The aim of the study. To establish a possible association between the skeletal muscles state, changes in lipid metabolism and the development of insulin resistance in children with type I diabetes mellitus. Materials and methods. 98 children with type 1 diabetes, aged from 11 to 17 years, were examined. Children were divided into 3 groups depending on the state of skeletal muscles: the first group – 22 children without disorders of the muscular system; the second group – 42 children with dynapenia; the third group – 34 patients with diabetic myopathy. The control group – 30 conditionally healthy children. The groups were representative by age, sex, and body mass index. Children were subjected to examinations of skeletal muscle mass and fat mass, followed by calculation of the skeletal muscle index and body fat percentage, sonomyography of the anterior group of thigh muscles with their thickness determination, measurements of the degree and coefficient of muscle hypotrophy, fasting blood glucose level, serum cholesterol, triglycerides and triglyceride-glucose (TyG) index. Insulin resistance was diagnosed when the TyG index was higher than 4.33 c. u. Results. It was found that the development of diabetic myopathy, in addition to a decrease in muscle mass, was characterized by a redistribution of the body component composition due an increase in the fat mass proportion. These changes were accompanied by a disturbance of lipid metabolism in the form of increase in serum cholesterol level, triglycerides and TyG index, which was 4.33 c. u. higher in 32.4 % of children with diabetic myopathy, and in 9.5 % of children with dynapenia, while among patients with normal state of the muscular system, the TyG index exceeded the threshold value in no case. Comparison of clinical and laboratory indicators depending on the TyG index level found an increase in the fat mass proportion, a violation of glycemic control, an increase in the daily dose of insulin, appearance of combined hyperlipidemia and the dawn phenomenon in children with an indicator that was higher than 4.33 c. u. All these were indicative of the insulin resistance development. Conclusions. Skeletal muscle dysfunction in children with type 1 diabetes is a causal risk factor for the development of insulin resistance, a sensitive marker of which is the TyG index. The simplicity of calculating this indicator allows it to be used in daily clinical practice.

Abstract P3132: High-salt Diet Increases Blood Cholesterol: Potential Role Of Hepatic Enzyme CYP51

Introduction: The increased consumption of dietary fat has been well established to lead to cardiovascular disease via the elevation of lipids in serum. High blood pressure is also commonly associated with high serum cholesterol levels, but the relationships among blood pressure, dietary sodium intake and serum cholesterol have not been fully elucidated. Hypothesis: An increase in the intake of salt causes an elevation of serum cholesterol through the activation of hepatic enzymes critical to cholesterol synthesis. Methods: Dahl salt-sensitive rats (n=6) were fed a high-salt (HS) diet (8% NaCl) from 7 weeks of age to induce hypertension. Rats fed a normal-salt (NS) diet (0.3% NaCl; n=6) served as controls. Blood pressure was measured non-invasively using a tail artery cuff. Blood was withdrawn from 6-hour fasting HS and NS-fed rats to check serum cholesterol levels. Low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very-low density lipoprotein (VLDL) cholesterols were measured. Gene expression array and western blot were performed in liver protein extracts from HS and NS-fed rats. Results: Systolic blood pressure was elevated in HS-fed rats compared to NS-fed rats at 16 weeks of age (225±23 vs. 156±18 mmHg, p=0.0002). Serum fasting cholesterol was higher in hypertensive rats compared to normotensive rats (194±49 vs. 102±12 mg/dL, p=0.0013). LDL cholesterol was higher in HS-fed rats compared to NS-fed rats (83±9 vs. 60±10 mg/dL, p=0.0024), while HDL and VLDL cholesterol were not. Hepatic cholesterol synthesis gene array revealed significant up-regulation of 3 genes in hypertensive rats in comparison to normotensive rats ( Apoa1 fold change [FC] 2.84, p<0.0001; Tm7sf2 FC 2.45, p=0.0004; Cyp51 FC 2.44, p=0.0002). Western blot of hepatic protein extracts showed a definitive increase in CYP51 in HS-fed rats compared to NS-fed rats (normalized against GAPDH, 2.7-fold increase, p=0.0018). Conclusions: A high-salt diet increased serum cholesterol levels, potentially via activation of liver enzyme CYP51, which is crucial for the synthesis of cholesterol in the liver. Further research is warranted to investigate the mechanisms of how high-salt diets can increase CYP51 in the liver.

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.

Mediterranean Fast Food: A Leading Cause of Hypercholesterolemia among University Students in Northern Jordan

Background:Consumption of fast food is pervasive among young adults. This research aimed to assess the impact of consuming fast foods on total cholesterol level among university students in Northern Jordan.Methods:Using a cross-sectional design, a blood sample to investigate cholesterol level was drawn from a sample of university students in Northern Jordan. Besides, students’ dietary habits and anthropometric measurements were obtained.Results:Out of 201 participants, 57% (n=115) were male and 43% (n=86) were female. More than three quarters of the sample ate shawarma (Mediterranean fast food) at least once per week. About 44% of the study subjects had increased BMI and about 37% had increased serum cholesterol level. Participants’ gender, age, marital status, physical activity, BMI, living status, and daily pocket money significantly correlated with cholesterol level (P<0.05). In the regression analysis, eating fast foods and increased BMI were strong predictors of high cholesterol level. Students who ate shawarma more than 3 times a week had more than 8 folds to have hypercholesterolemia (OR=8.4; CI: 2.62–26.72), and obese students were more than 14 folds at higher risk to have hypercholesterolemia compared to those with normal BMI (OR=14.2; CI: 4.80–42.29). In addition, male students had doubled odds for having abnormal cholesterol level compared to females (OR=2.1; CI: 1.10–4.44).Conclusion:Fast food consumption among university students in Jordan was significantly associated with increased total cholesterol level. Encouraging healthy diet and lifestyle are the basis for prevention of dyslipidemia.

Factors Affecting the Occurrence of Coronary Heart Disease in the General Hospital of Waikabubak, Indonesia

Coronary heart disease (CHD) causes many deaths. It is a disease of the heart that occurs due to decreased blood supply to the heart muscle. Risk factors that can trigger CHD can be grouped into two categories, namely those that cannot be modified and those that can. The risk factors that cannot be modified include heredity, age and gender, while the modifiable risk factors include smoking, hypertension, increased serum cholesterol levels, obesity and diabetes. Basic Health Research data show that in 2018, 1.5% or 15 out of 1000 Indonesians suffered from CHD. The aim of this study was to investigate the factors that influence the incidence of CHD at the RSUD Waikabubak. This was a quantitative analytical survey which used a cross-sectional approach. According to the results, CHD was significantly associated with gender (OR = 3.5, p = 0.011), smoking (OR = 3.9, p = 0.006) and hypertension (OR = 4.8, p = 0.001). Of the factors studied, hypertension had the strongest influence on the incidence of CHD.&#x0D; Keywords: coronary heart disease, the factors that influence

The effects of valproate on serum leptin, insulin, and lipid levels in epileptic children.

Weight gain is an important adverse effect of valproate (VPA) therapy. A number of mechanisms have been proposed for its pathophysiology. The aim of the present study is the evaluation of insulin, leptin and lipid levels in epileptic children on treatment with VPA. Thirty epileptic children treated with VPA, and 20 age-sex-matched healthy children, were enrolled in this study. Blood samples were taken and the body mass index was calculated for all of the subjects. Serum insulin, leptin, and lipid levels were compared between the two groups. Leptin levels were significantly higher in the patient group (P = 0.009) whereas body mass index values were comparable. There was a positive correlation between leptin and body mass index among both patient (r = 0.464, P = 0.01) and control groups (r = 0.734, P = 0.0001). Total cholesterol and low-density lipoprotein (LDL) cholesterol levels were lower in VPA-treated epileptic children than the control group (P = 0.008; P = 0.003, respectively). No significant difference was determined in insulin levels between the two groups. A negative correlation was observed between plasma VPA level and total cholesterol and LDL cholesterol levels in the patient group (r = -0.380, P = 0.03, r = -0.474, P = 0.008, respectively). This study demonstrated higher leptin levels in the patient group despite similar BMI values. Hence, it seems likely that VPA causes leptin resistance. Unlike other anti-epileptics, VPA does not produce an increase in serum cholesterol levels. On the contrary, lower levels of total and LDL cholesterol levels in VPA-receiving patients have been observed in our study.

Clinical, Laboratory, Instrumental, Anamnestic Characteristics in Children With Type I Diabetes Mellitus and Early Stage of Diabetic Nephropathy.

Type 1 diabetes (T1D) is mainly a disease of children and young adults. Diabetic nephropathy (DN) is a common finding in diabetic patients. Microalbuminuria is the earliest clinical evidence of DN. Aim of the study was analysis of clinical, laboratory, instrumental, anamnestic examinations data in pediatric patients with T1D and early stage of DN in order to evaluate possible factors associated with early stage of DN and predictors of DN development and progression. A survey of 105 children (62 males, 43 females) with T1D and DN aged 5 to 17 years in Endocrinology unit on Clinical Pediatric Hospital №6 (Kyiv, Ukraine) done. Following clinical and biochemical characteristics found associated with an early DN: inflammatory phenotype (increased ESR, decreased albumin/globulin ratio), functional cardiovascular disorders (increased systolic blood pressure, “minor” ECG changes), signs of secondary metabolic disorders (high HbA1c, increased serum cholesterol level, increase ALAT and ASAT levels). Kidney function impairment at early stage of DN shows: higher MAU grade, GFR decline, rise in serum creatinine level as compared to T1D group. Presence of concomitant kidney and endocrine disease; positive family history found in a bigger number of patients with DN. DKA episodes number found as a factor associated with higher levels of MAU in children with DN. Patients who had microalbuminuria and more than 5 episodes of DKA/year (poorly controlled T1D) have higher progression rate to macroalbuminuria as compared to those who have less than 5 episodes of DKA/year after a 6-year follow-up study.

Sleep Disturbance Induces Increased Cholesterol Level by NR1D1 Mediated CYP7A1 Inhibition.

Disturbed sleep is closely associated with an increased risk of metabolic diseases. However, the underlying mechanisms of circadian clock genes linking sleep and lipid profile abnormalities have not been fully elucidated. This study aimed to explore the important role of the circadian clock in regulating impaired cholesterol metabolism at an early stage of sleep deprivation (SD). Sleep disturbance was conducted using an SD instrument. Our results showed that SD increased the serum cholesterol levels. Concentrations of serum leptin and resistin were much lower after SD, but other metabolic hormone concentrations (adiponectin, glucagon, insulin, thyroxine, norepinephrine, and epinephrine) were unchanged before and after SD. Warning signs of cardiovascular diseases [decreased high density lipoprotein (HDL)-cholesterol and increased corticosterone and 8-hydroxyguanosine levels] and hepatic cholestasis (elevated total bile acids and bilirubin levels) were observed after SD. Cholesterol accumulation was also observed in the liver after SD. The expression levels of HMGCR, the critical enzyme for cholesterol synthesis, remained unchanged in the liver. However, the expression levels of liver CYP7A1, the enzyme responsible for the conversion of cholesterol into bile acids, significantly reduced after SD. Furthermore, expression of NR1D1, a circadian oscillator and transcriptional regulator of CYP7A1, strikingly decreased after SD. Moreover, NR1D1 deficiency decreased liver CYP7A1 levels, and SD could exacerbate the reduction of CYP7A1 expression in NR1D1−/− mouse livers. Additionally, NR1D1 deficiency could further increase serum cholesterol levels under SD. These results suggest that sleep disturbance can induce increased serum cholesterol levels and liver cholesterol accumulation by NR1D1 mediated CYP7A1 inhibition.

Hypolipaemic nutraceutics: red yeast rice and Armolipid, berberine and bergamot.

Increased serum cholesterol levels constitute one of the main risk factors for cardiovascular diseases. Statins are a major method for reducing the levels which also lower the risk of cardiovascular events. However, these valuable drugs cannot be used in all patients who need them due to contraindications and intolerance. In such cases, help can be sought from nutraceutics that reduce the serum cholesterol concentration. Since there are numerous products of this type available at drugstores, registered as supplements, there seems to be a need to demonstrate their effectiveness in preventing cardiovascular diseases induced by atherosclerosis. In literature, increasingly more attention is drawn to red yeast rice, Armolipid, berberine and bergamot. This article presents knowledge about these nutraceutics based on clinical studies and expert statements relating to their use. The results of clinical studies and metaanalyses have shown that nutraceutics with cholesterol lowering properties, red yeast rice and Armolipid are the most favourable for reducing cardiovascular events. However, the evidence of benefits of berberine and bergamot is not so conclusive. Red yeast rice products and Armolipid may be used as an alternative treatment in statin intolerant patients, especially in combination with ezetimibe. These nutraceutics can be also considered, as an adjunct to diet therapy in primary prevention of cardiovascular diseases in patients with mild and moderate hypercholesterolaemia. The opinion of experts on berberine and bergamot is ambiguous.

Loss of CTRP4 alters adiposity and food intake behaviors in obese mice.

Central and peripheral mechanisms are both required for proper control of energy homeostasis. Among circulating plasma proteins, C1q/TNF-related proteins (CTRPs) have recently emerged as important regulators of sugar and fat metabolism. CTRP4, expressed in brain and adipose tissue, is unique among the family members in having two tandem globular C1q domains. We previously showed that central administration of recombinant CTRP4 suppresses food intake, suggesting a central nervous system role in regulating ingestive physiology. Whether this effect is pharmacological or physiological remains unclear. We used a loss-of-function knockout (KO) mouse model to clarify the physiological role of CTRP4. Under basal conditions, CTRP4 deficiency increased serum cholesterol levels and impaired glucose tolerance in male but not female mice fed a control low-fat diet. When challenged with a high-fat diet, male and female KO mice responded differently to weight gain and had different food intake patterns. On an obesogenic diet, male KO mice had similar weight gain as wild-type littermates. When fed ad libitum, KO male mice had greater meal number, shorter intermeal interval, and reduced satiety ratio. Female KO mice, in contrast, had lower body weight and adiposity. In the refeeding period following food deprivation, female KO mice had significantly higher food intake due to longer meal duration and reduced satiety ratio. Collectively, our data provide genetic evidence for a sex-dependent physiological role of CTRP4 in modulating food intake patterns and systemic energy metabolism.

Comprehensive Characterization of the Vascular Effects of Cisplatin-Based Chemotherapy in Patients With Testicular Cancer

BackgroundCisplatin-based chemotherapy increases the risk of cardiovascular and renal disease. ObjectivesWe aimed to define the time course, pathophysiology, and approaches to prevent cardiovascular disease associated with cisplatin-based chemotherapy. MethodsTwo cohorts of patients with a history of testicular cancer (n = 53) were recruited. Cohort 1 consisted of 27 men undergoing treatment with: 1) surveillance; 2) 1 to 2 cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy (low-intensity cisplatin); or 3) 3 to 4 cycles of BEP (high-intensity cisplatin). Endothelial function (percentage flow-mediated dilatation) and cardiovascular biomarkers were assessed at 6 visits over 9 months. Cohort 2 consisted of 26 men previously treated 1 to 7 years ago with surveillance or 3 to 4 cycles BEP. Vasomotor and fibrinolytic responses to bradykinin, acetylcholine, and sodium nitroprusside were evaluated using forearm venous occlusion plethysmography. ResultsIn cohort 1, the percentage flow-mediated dilatation decreased 24 h after the first cisplatin dose in patients managed with 3 to 4 cycles BEP (10.9 ± 0.9 vs. 16.7 ± 1.6; p < 0.01) but was unchanged from baseline thereafter. Six weeks after starting 3 to 4 cycles BEP, there were increased serum cholesterol levels (7.2 ± 0.5 mmol/l vs. 5.5 ± 0.2 mmol/l; p = 0.01), hemoglobin A1c (41.8 ± 2.0 mmol/l vs. 35.5 ± 1.2 mmol/l; p < 0.001), von Willebrand factor antigen (62.4 ± 5.4 mmol/l vs. 45.2 ± 2.8 mmol/l; p = 0.048) and cystatin C (0.91 ± 0.07 mmol/l vs. 0.65 ± 0.09 mmol/l; p < 0.01). In cohort 2, intra-arterial bradykinin, acetylcholine, and sodium nitroprusside caused dose-dependent vasodilation (p < 0.0001). Vasomotor responses, endogenous fibrinolytic factor release, and cardiovascular biomarkers were not different in patients managed with 3 to 4 cycles of BEP versus surveillance. ConclusionsCisplatin-based chemotherapy induces acute and transient endothelial dysfunction, dyslipidemia, hyperglycemia, and nephrotoxicity in the early phases of treatment. Cardiovascular and renal protective strategies should target the early perichemotherapy period. (Clinical Characterisation of the Vascular Effects of Cis-platinum Based Chemotherapy in Patients With Testicular Cancer [VECTOR], NCT03557177; Intermediate and Long Term Vascular Effects of Cisplatin in Patients With Testicular Cancer [INTELLECT], NCT03557164)