An overview of the cholesterol metabolism and its proinflammatory role in the development of MASLD.

Cholesterol is an essential lipid molecule in mammalian cells. It is not only involved in the formation of cell membranes but also serves as a raw material for the synthesis of bile acids, vitamin D, and steroid hormones. Additionally, it acts as a covalent modifier of proteins and plays a crucial role in numerous life processes. Generally, the metabolic processes of cholesterol absorption, synthesis, conversion, and efflux are strictly regulated. Excessive accumulation of cholesterol in the body is a risk factor for metabolic diseases such as cardiovascular disease, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). In this review, we first provide an overview of the discovery of cholesterol and the fundamental process of cholesterol metabolism. We then summarize the relationship between dietary cholesterol intake and the risk of developing MASLD, and also the animal models of MASLD specifically established with a cholesterol-containing diet. In the end, the role of cholesterol-induced inflammation in the initiation and development of MASLD is discussed.

Associations of Dietary Cholesterol Consumption With Incident Diabetes and Cardiovascular Disease: The Role of Genetic Variability in Cholesterol Absorption and Disease Predisposition.

OBJECTIVE: Whether genetic susceptibility to disease and dietary cholesterol (DC) absorption contribute to inconsistent associations of DC consumption with diabetes and cardiovascular disease (CVD) remains unclear. RESEARCH DESIGN AND METHODS: DC consumption was assessed by repeated 24-h dietary recalls in the UK Biobank. A polygenetic risk score (PRS) for DC absorption was constructed using genetic variants in the Niemann-Pick C1-Like 1 and ATP Binding Cassettes G5 and G8 genes. PRSs for diabetes, coronary artery disease, and stroke were also created. The associations of DC consumption with incident diabetes (n = 96,826) and CVD (n = 94,536) in the overall sample and by PRS subgroups were evaluated using adjusted Cox models. RESULTS: Each additional 300 mg/day of DC consumption was associated with incident diabetes (hazard ratio [HR], 1.17 [95% CI, 1.07-1.27]) and CVD (HR, 1.09 [95% CI, 1.03-1.17]), but further adjusting for BMI nullified these associations (HR for diabetes, 0.99 [95% CI, 0.90-1.09]; HR for CVD, 1.04 [95% CI, 0.98-1.12]). Genetic susceptibility to the diseases did not modify these associations (P for interaction ≥0.06). The DC-CVD association appeared to be stronger in people with greater genetic susceptibility to cholesterol absorption assessed by the non-high-density lipoprotein cholesterol-related PRS (P for interaction = 0.04), but the stratum-level association estimates were not statistically significant. CONCLUSIONS: DC consumption was not associated with incident diabetes and CVD, after adjusting for BMI, in the overall sample and in subgroups stratified by genetic predisposition to cholesterol absorption and the diseases. Nevertheless, whether genetic predisposition to cholesterol absorption modifies the DC-CVD association requires further investigation.

A high-cholesterol diet promotes the intravasation of breast tumor cells through an LDL-LDLR axis.

Most metastases in breast cancer occur via the dissemination of tumor cells through the bloodstream. How tumor cells enter the blood (intravasation) is, however, a poorly understood mechanism at the cellular and molecular levels. Particularly uncharacterized is how intravasation is affected by systemic nutrients. High levels of systemic LDL-cholesterol have been shown to contribute to breast cancer progression and metastasis in various models, but the cellular and molecular mechanisms involved are still undisclosed. Here we show that a high- cholesterol diet promotes intravasation in two mouse models of breast cancer and that this could be reverted by blocking LDL binding to LDLR in tumor cells. Moreover, we show that LDL promotes vascular invasion in vitro and the intercalation of tumor cells with endothelial cells, a phenotypic change resembling vascular mimicry (VM). At the molecular level, LDL increases the expression of SERPINE2, previously shown to be required for both VM and intravasation. Overall, our manuscript unravels novel mechanisms by which systemic hypercholesterolemia may affect the onset of metastatic breast cancer by favouring phenotypic changes in breast cancer cells and increasing intravasation.

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

BACKGROUND AND AIMS: Although 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 RESULTS: The 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. CONCLUSION: Although 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 Intake of Dietary Cholesterol Decreases the Risk of All-Cause Dementia and AD Dementia: A Results from Framingham Offspring Cohort.

BACKGROUND: Dietary cholesterol has been confirmed to be associated with high risks of diabetes, hypertension, and stroke, but whether it is detrimental to cognitive health is highly debated. This study aimed to investigate the associations between dietary cholesterol and all-cause dementia and AD dementia. METHODS: This prospective study analyzed Framingham Offspring Study cohort (FOS) participants who were dementia-free at baseline and had detailed information on daily diet (measured by food frequency questionnaires) and demographic characteristics. Surveillance for incident dementia commenced at examination 5 (1991-1995) through 2018 and continued for approximately 30 years. RESULTS: A total of 3249 subjects were included with a mean age of 54.7 years (SD: 9.8). During a median follow-up of 20.2 years (interquartile range: 14.2-24.8), a total of 312 incident dementia events occurred, including 211 (67.7%) cases of AD dementia. After multivariate adjustments for established dementia risk factors, participants with the highest intake of dietary cholesterol had a lower risk of all-cause dementia (HR: 0.70; 95% CI: 0.57-0.93) and AD dementia (HR: 0.68; 95% CI: 0.60-0.88) relative to individuals with the lowest intake. However, the associations were not significant for the group with a medium intake of dietary cholesterol. CONCLUSION: High intake of dietary cholesterol was associated with a decreased risk of all-cause dementia and AD dementia. The findings of this observational study need to be confirmed by other studies to highlight the role of dietary cholesterol in the development of neurodegenerative diseases.

From Dietary Cholesterol to Blood Cholesterol.

The Nutrients' Special Issue "From dietary cholesterol to blood cholesterol" aims to supply existing knowledge and novel new research data about human cholesterol (C) fluxes [...].

Stigmasterol Protects Against Steatohepatitis Induced by High-Fat and High-Cholesterol Diet in Mice by Enhancing the Alternative Bile Acid Synthesis Pathway.

BACKGROUND: Hepatic cholesterol accumulation is a significant risk factor in the progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis. However, the precise mechanism by which stigmasterol (STG) mitigates this process remains unclear. OBJECTIVES: This study aimed to investigate the potential mechanism underlying the protective effect of STG in mice with NAFLD progressing to steatohepatitis while being fed a high-fat and high-cholesterol (HFHC) diet. METHODS: Male C57BL/6 mice were fed an HFHC diet for 16 wk to establish the NAFLD model. Subsequently, the mice received STG or a vehicle via oral gavage while continuing the HFHC diet for an additional 10 wk. The study evaluated hepatic lipid deposition and inflammation as well as the expression of key rate-limiting enzymes involved in the bile acid (BA) synthesis pathways. BAs in the colonic contents were quantified using ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: Compared with the vehicle control group, STG significantly reduced hepatic cholesterol accumulation (P < 0.01) and suppressed the gene expression of NLRP3 inflammasome and interleukin-18 (P < 0.05) in the livers of HFHC diet-fed mice. The total fecal BA content in the STG group was nearly double that of the vehicle control group. Additionally, the administration of STG increased the concentrations of representative hydrophilic BAs in the colonic contents (P < 0.05) along with the upregulation of gene and protein expression of CYP7B1 (P < 0.01). Furthermore, STG enhanced the α-diversity of the gut microbiota and partially reversed the alterations in the relative abundance of the gut microbiota induced by the HFHC diet. CONCLUSIONS: STG mitigates steatohepatitis by enhancing the alternative pathway for BA synthesis.

Proteomics Analysis of Lipid Metabolism and Inflammatory Response in the Liver of Rabbits fed on a High Cholesterol Diet.

In this study, we aimed to analyze the proteomics of the liver in rabbits on a high cholesterol diet (HCD). We randomly divided New Zealand white rabbits into the normal diet group and the HCD group. We established the atherosclerosis model and measured plasma cholesterol and triglycerides. The model was successfully established using ultrasound examination and histopathological staining of the intima of aorta and liver of the two groups of rabbits. The differential proteins in the rabbit liver were analyzed using Tandem Mass Tags proteomic analysis technology. Finally, we used western blot to verify the reliability of proteomics. The results showed that compared with the control group, the serum lipid levels of rats in the HCD group was significantly increased, and the pathological sections showed the formation of atherosclerotic plaques in the aorta, inflammation, and adipose lesions in the liver. Proteomic analysis of the liver revealed 149 differences in HCD-expressed protein, which is mainly involved in inflammation and regulation of lipid and sugar metabolism. In addition, we verified differentially expressed liver proteins in the HCD group using western blot. We found that HCD caused lipid accumulation, abnormal glucose metabolism, and inflammatory response in the liver.

Dietary cholesterol drives the development of nonalcoholic steatohepatitis by altering gut microbiota mediated bile acid metabolism in high-fat diet fed mice.

Nonalcoholic fatty liver disease (NAFLD) is the most widespread chronic liver disorder globally. Unraveling the pathogenesis of simple fatty liver to nonalcoholic steatohepatitis (NASH) has important clinical significance for improving the prognosis of NAFLD. Here, we explored the role of a high-fat diet alone or combined with high cholesterol in causing NASH progression. Our results demonstrated that high dietary cholesterol intakes accelerate the progression of spontaneous NAFLD and induces liver inflammation in mice. An elevation of hydrophobic unconjugated bile acids cholic acid (CA), deoxycholic acid (DCA), muricholic acid and chenodeoxycholic acid, was observed in high-fat and high-cholesterol diet fed mice. Full-length sequencing of the 16S rDNA gene of gut microbiota revealed a significant increase in the abundance of Bacteroides, Clostridium, and Lactobacillus that possess bile salt hydrolase activity. Furthermore, the relative abundance of these bacterial species was positively correlated with content of unconjugated bile acids in liver. Moreover, the expression of genes related to bile acid reabsorption (organic anion-transporting polypeptides, Na+-taurocholic acid cotransporting polypeptide, apical sodium dependent bile acid transporter and organic solute transporter ß) was found to be increased in mice with a high-cholesterol diet. Lastly, we observed that hydrophobic bile acids CA and DCA induce an inflammatory response in free fatty acids-induced steatotic HepG2 cells. In conclusion, high dietary cholesterol promotes the development of NASH by altering gut microbiota composition and abundance and thereby influencing with bile acid metabolism.

Dietary cholesterol consumption and incidence of type 2 diabetes mellitus: A dose-response meta-analysis of prospective cohort studies.

BACKGROUND AND AIM: The purpose of this meta-analysis was to evaluate the dose-response relationship between dietary cholesterol (DC) consumption and the incidence of type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: Prospective studies with the endpoint of T2DM were included. The Random-effect model weighted by inverse variance was used. Meta-regression and subgroup analyses were conducted to explore the potential sources of heterogeneity by specified study characteristics. Restricted cubic splines regression models were used to estimate the dose-response relationship. 11 prospective studies comprising of 355 230 subjects were included. Compared to lowest DC consumption, highest DC consumption was associated with an increased risk of T2DM (RR 1.15, 95% CI 1.03 to 1.28, P = 0.012; chi-squared = 31.41, I-squared 58.6%, P heterogeneity = 0.003). Subgroup analyses have shown that this positive association was more evident in western countries than in eastern countries (RR 1.19, 95% CI 1.06 to 1.36 VS 1.34, 95% CI 0.84 to 1.29; P subgroup difference = 0.02). For 100 mg/d increment in DC intake, the pooled RR was 1.05, (95% CI 1.04 to 1.07, Plinearity = 0.000, Pnonlinearity = 0.02), 1.06 (95% CI 1.04 to 1.07, Plinearity=0.000), and 1.01 (95% CI 0.98 to 1.05, Plinearity = 0.525) for the incidence of T2DM, in western and eastern countries, respectively. CONCLUSIONS: Our study suggests that there is a positive dose-response association between DC consumption and the incidence of T2DM, especially in western countries. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020216318.

The Association of Dietary Cholesterol from Egg Consumption on Cardiovascular Diseases Risk Varies from Person to Person.

The public and scientists remain skeptical about egg consumption, given that cardiovascular diseases (CVDs) are the leading causes of death in worldwide. This review mainly explained the recurrence of contradictory conclusions about relationships between egg consumption and CVD risk and discussed effects of egg cholesterol intake on cholesterol homeostasis. Factors including individual health status and cholesterol sensitivity, dietary pattern, region, and race should be distinguished when understanding generalized conclusions. Identified compensatory mechanisms in response to dietary cholesterol and the resulting balance in cholesterol biosynthesis, absorption, and efflux supported the view that moderate egg consumption had no substantial overall impacts on cholesterol homeostasis in healthy people. Excessive cholesterol intake is not recommended in individuals with distempered metabolism. More than cholesterol metabolism, impacts of egg consumption as a part of overall diet on CVD risk should be considered from aspects of nutrient intake, lipid metabolism, and energy supply in the future.

Hepatic damage caused by long-term high cholesterol intake induces a dysfunctional restorative macrophage population in experimental NASH.

Excessive dietary cholesterol is preferentially stored in the liver, favoring the development of nonalcoholic steatohepatitis (NASH), characterized by progressive hepatic inflammation and fibrosis. Emerging evidence indicates a critical contribution of hepatic macrophages to NASH severity. However, the impact of cholesterol on these cells in the setting of NASH remains elusive. Here, we demonstrate that the dietary cholesterol content directly affects hepatic macrophage global gene expression. Our findings suggest that the modifications triggered by prolonged high cholesterol intake induce long-lasting hepatic damage and support the expansion of a dysfunctional pro-fibrotic restorative macrophage population even after cholesterol reduction. The present work expands the understanding of the modulatory effects of cholesterol on innate immune cell transcriptome and may help identify novel therapeutic targets for NASH intervention.

Dietary Cholic Acid Exacerbates Liver Fibrosis in NASH Model of Sprague-Dawley Rats Fed a High-Fat and High-Cholesterol Diet.

BACKGROUND: Recently, we established a novel rodent model of nonalcoholic steatohepatitis (NASH) with advanced fibrosis induced by a high-fat and high-cholesterol (HFC) diet containing cholic acid (CA), which is known to cause hepatotoxicity. The present study aimed to elucidate the direct impact of dietary CA on the progression of NASH induced by feeding the HFC diet. METHODS: Nine-week-old male Sprague-Dawley rats were randomly assigned to receive a normal, HFC, or CA-supplemented (0.1%, 0.5% or 2.0%, w/w) HFC diet for 9 weeks. RESULTS: Histopathological assessment revealed that the supplementation of CA dose-dependently aggravated hepatic steatosis, inflammation, and fibrosis, reaching stage 4 cirrhosis in the 2.0% CA diet group. In contrast, the rats that were fed the HFC diet without any added CA developed mild steatosis and inflammation without fibrosis. The hepatic cholesterol content and mRNA expression involved in inflammatory response and fibrogenesis was higher in a CA dose-dependent manner. The hepatic chenodeoxycholic acid levels were higher in 2.0% CA diet group than in the control, although hepatic levels of total bile acid and CA did not increase dose-dependently with CA intake. CONCLUSION: Adding CA to the HFC diet altered bile acid metabolism and inflammatory response and triggered the development of fibrosis in the rat liver.

Is There a Correlation between Dietary and Blood Cholesterol? Evidence from Epidemiological Data and Clinical Interventions.

Dietary cholesterol has been a topic of debate since the 1960s when the first dietary guidelines that limited cholesterol intake to no more than 300 mg/day were set. These recommendations were followed for several years, and it was not until the late 1990s when they were finally challenged by the newer information derived from epidemiological studies and meta-analysis, which confirmed the lack of correlation between dietary and blood cholesterol. Further, dietary interventions in which challenges of cholesterol intake were evaluated in diverse populations not only confirmed these findings but also reported beneficial effects on plasma lipoprotein subfractions and size as well as increases in HDL cholesterol and in the functionality of HDL. In this review, we evaluate the evidence from recent epidemiological analysis and meta-analysis as well as clinical trials to have a better understanding of the lack of correlation between dietary and blood cholesterol.

Association of dietary cholesterol and dyslipidemia in Chinese health examinees.

BACKGROUND: The association between dietary cholesterol consumption and dyslipidemia is still in controversy. The study aims to evaluate whether dietary cholesterol intake associated with dyslipidemia and its components in Chinese health examinees. METHODS: A large-scale cross-sectional study was conducted among health examinees of in Shaanxi province. Totally of 8358 participants (3677 male and 4681 female) were included. Dietary cholesterol intake was assessed by validated food frequency questionnaire. Multivariable regression and restricted cubic spline models were used to capture the linear and non-linear association between dietary cholesterol and dyslipidemia. RESULTS: A total of 2429 (29.1%) subjects were newly diagnosed of dyslipidemia, the prevalence was 29.2% in male and 27.7% in female. Mean intake of dietary cholesterol was 213.7 mg/day. After adjusting for all potential confounders including demographics information and lifestyles, higher cholesterol consumption was related to lower risk of dyslipidemia, the ORs (95% CIs) across Q2 to Q4 group were 0.87 (0.60-1.26), 0.80 (0.55-1.18) and 0.61 (0.41-0.91) in female. With further controlling for nutrients principal components, a null association was observed between dietary cholesterol and dyslipidemia and serum lipids, regardless of gender. Results of restricted cubic splines showed that the risk of dyslipidemia decreased slowly until around 300 mg/day in men and 200 mg/day in women, although the non-linear association was not significant. CONCLUSIONS: The study suggested that dietary cholesterol consumption was not associated with dyslipidemia or serum lipids in Chinese health examinees, although a decreased risk was observed before the threshold points.

Dietary Cholesterol Causes Inflammatory Imbalance and Exacerbates Morbidity in Mice Infected with Influenza A Virus.

Influenza is a common cause of pneumonia-induced hospitalization and death, but how host factors function to influence disease susceptibility or severity has not been fully elucidated. Cellular cholesterol levels may affect the pathogenesis of influenza infection, as cholesterol is crucial for viral entry and replication, as well as immune cell proliferation and function. However, there is still conflicting evidence on the extent to which dietary cholesterol influences cholesterol metabolism. In this study, we examined the effects of a high-cholesterol diet in modulating the immune response to influenza A virus (IAV) infection in mice. Mice were fed a standard or a high-cholesterol diet for 5 wk before inoculation with mouse-adapted human IAV (Puerto Rico/8/1934), and tissues were collected at days 0, 4, 8, and 16 postinfection. Cholesterol-fed mice exhibited dyslipidemia characterized by increased levels of total serum cholesterol prior to infection and decreased triglycerides postinfection. Cholesterol-fed mice also displayed increased morbidity compared with control-fed mice, which was neither a result of immunosuppression nor changes in viral load. Instead, transcriptomic analysis of the lungs revealed that dietary cholesterol caused upregulation of genes involved in viral-response pathways and leukocyte trafficking, which coincided with increased numbers of cytokine-producing CD4+ and CD8+ T cells and infiltrating dendritic cells. Morbidity as determined by percent weight loss was highly correlated with numbers of cytokine-producing CD4+ and CD8+ T cells as well as granulocytes. Taken together, dietary cholesterol promoted IAV morbidity via exaggerated cellular immune responses that were independent of viral load.

From Dietary Cholesterol to Blood Cholesterol, Physiological Lipid Fluxes, and Cholesterol Homeostasis.

Dietary cholesterol (C) is a major contributor to the endogenous C pool, and it affects the serum concentration of total C, particularly the low-density lipoprotein cholesterol (LDL-C). A high serum concentration of LDL-C is associated with an increased risk for atherosclerosis and cardiovascular diseases. This concentration is dependent on hepatic C metabolism creating a balance between C input (absorption and synthesis) and C elimination (conversion to bile acids and fecal excretion). The daily C absorption rate is determined by dietary C intake, biliary C secretion, direct trans-intestinal C excretion (TICE), and the fractional C absorption rate. Hepatic C metabolism coordinates C fluxes entering the liver via chylomicron remnants (CMR), LDL, high-density lipoproteins (HDL), hepatic C synthesis, and those leaving the liver via very low-density lipoproteins (VLDL), biliary secretion, and bile acid synthesis. The knowns and the unknowns of this C homeostasis are discussed.