Lipid metabolism within the bone micro-environment is closely associated with bone metabolism in physiological and pathophysiological stages.

Recent advances in society have resulted in the emergence of both hyperlipidemia and obesity as life-threatening conditions in people with implications for various types of diseases, such as cardiovascular diseases and cancer. This is further complicated by a global rise in the aging population, especially menopausal women, who mostly suffer from overweight and bone loss simultaneously. Interestingly, clinical observations in these women suggest that osteoarthritis may be linked to a higher body mass index (BMI), which has led many to believe that there may be some degree of bone dysfunction associated with conditions such as obesity. It is also common practice in many outpatient settings to encourage patients to control their BMI and lose weight in an attempt to mitigate mechanical stress and thus reduce bone pain and joint dysfunction. Together, studies show that bone is not only a mechanical organ but also a critical component of metabolism, and various endocrine functions, such as calcium metabolism. Numerous studies have demonstrated a relationship between metabolic dysfunction in bone and abnormal lipid metabolism. Previous studies have also regarded obesity as a metabolic disorder. However, the relationship between lipid metabolism and bone metabolism has not been fully elucidated. In this narrative review, the data describing the close relationship between bone and lipid metabolism was summarized and the impact on both the normal physiology and pathophysiology of these tissues was discussed at both the molecular and cellular levels.

Multiomic analysis of the Arabian camel (Camelus dromedarius) kidney reveals a role for cholesterol in water conservation.

The Arabian camel (Camelus dromedarius) is the most important livestock animal in arid and semi-arid regions and provides basic necessities to millions of people. In the current context of climate change, there is renewed interest in the mechanisms that enable camelids to survive in arid conditions. Recent investigations described genomic signatures revealing evolutionary adaptations to desert environments. We now present a comprehensive catalogue of the transcriptomes and proteomes of the dromedary kidney and describe how gene expression is modulated as a consequence of chronic dehydration and acute rehydration. Our analyses suggested an enrichment of the cholesterol biosynthetic process and an overrepresentation of categories related to ion transport. Thus, we further validated differentially expressed genes with known roles in water conservation which are affected by changes in cholesterol levels. Our datasets suggest that suppression of cholesterol biosynthesis may facilitate water retention in the kidney by indirectly facilitating the AQP2-mediated water reabsorption.

Liver Lipids of Patients with Hepatitis B and C and Associated Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) still remains a difficult to cure malignancy. In recent years, the focus has shifted to lipid metabolism for the treatment of HCC. Very little is known about hepatitis B virus (HBV) and C virus (HCV)-related hepatic lipid disturbances in non-malignant and cancer tissues. The present study showed that triacylglycerol and cholesterol concentrations were similar in tumor adjacent HBV and HCV liver, and were not induced in the HCC tissues. Higher levels of free cholesterol, polyunsaturated phospholipids and diacylglycerol species were noted in non-tumorous HBV compared to HCV liver. Moreover, polyunsaturated phospholipids and diacylglycerols, and ceramides declined in tumors of HBV infected patients. All of these lipids remained unchanged in HCV-related HCC. In HCV tumors, polyunsaturated phosphatidylinositol levels were even induced. There were no associations of these lipid classes in non-tumor tissues with hepatic inflammation and fibrosis scores. Moreover, these lipids did not correlate with tumor grade or T-stage in HCC tissues. Lipid reprogramming of the three analysed HBV/HCV related tumors mostly resembled HBV-HCC. Indeed, lipid composition of non-tumorous HCV tissue, HCV tumors, HBV tumors and HBV/HCV tumors was highly similar. The tumor suppressor protein p53 regulates lipid metabolism. The p53 and p53S392 protein levels were induced in the tumors of HBV, HCV and double infected patients, and this was significant in HBV infection. Negative correlation of tumor p53 protein with free cholesterol indicates a role of p53 in cholesterol metabolism. In summary, the current study suggests that therapeutic strategies to target lipid metabolism in chronic viral hepatitis and associated cancers have to consider disease etiology.

A Timing Effect of 17-ß Estradiol on Atherosclerotic Lesion Development in Female ApoE-/- Mice.

Differences in size or composition of existing plaques at the initiation of estrogen (E2) therapy may underpin evidence of increased risk of atherosclerosis-associated clinical sequelae. We investigated whether E2 had divergent effects on actively-growing versus established-advanced atherosclerotic lesions. Eight weeks of subcutaneous bi-weekly injections of 3 µg/g 17ß-estradiol (n = 18) or vehicle control (n = 22) were administered to female Apolipoprotein null-mice aged 25- or 45 weeks old. Histological assessment of lesion size within the brachiocephalic artery was conducted. Lesion composition was also assessed with acellular, calcification and fibrosis areas measured and other cellular features (intimal thickening, foam cells, lipid pools and cholesterol) scored (0-3) for severity. The comparison showed increased lesion size and calcified area with advancing age but no effect of E2. However, subtle changes in composition were observed following E2. Within the younger group, E2 increased intima thickening and acceleration of calcification. In the older group, E2 increased the thickness of the lesion cap. Therefore, this study shows different effects of E2 depending on the underlying stage of lesion development at the time of initiation of treatment. These divergent changes help explain the controversy of the adverse effects of E2 treatment in cardiovascular disease.

Altered Lipid Domains Facilitate Enhanced Pulmonary Vasoconstriction after Chronic Hypoxia.

Chronic hypoxia (CH) augments depolarization-induced pulmonary vasoconstriction through superoxide-dependent, Rho kinase-mediated Ca2+ sensitization. Nicotinamide adenine dinucleotide phosphate oxidase and EGFR (epidermal growth factor receptor) signaling contributes to this response. Caveolin-1 regulates the activity of a variety of proteins, including EGFR and nicotinamide adenine dinucleotide phosphate oxidase, and membrane cholesterol is an important regulator of caveolin-1 protein interactions. We hypothesized that derangement of these membrane lipid domain components augments depolarization-induced Ca2+ sensitization and resultant vasoconstriction after CH. Although exposure of rats to CH (4 wk, ∼380 mm Hg) did not alter caveolin-1 expression in intrapulmonary arteries or the incidence of caveolae in arterial smooth muscle, CH markedly reduced smooth muscle membrane cholesterol content as assessed by filipin fluorescence. Effects of CH on vasoreactivity and superoxide generation were examined using pressurized, Ca2+-permeabilized, endothelium-disrupted pulmonary arteries (∼150 µm inner diameter) from CH and control rats. Depolarizing concentrations of KCl evoked greater constriction in arteries from CH rats than in those obtained from control rats, and increased superoxide production as assessed by dihydroethidium fluorescence only in arteries from CH rats. Both cholesterol supplementation and the caveolin-1 scaffolding domain peptide antennapedia-Cav prevented these effects of CH, with each treatment restoring membrane cholesterol in CH arteries to control levels. Enhanced EGF-dependent vasoconstriction after CH similarly required reduced membrane cholesterol. However, these responses to CH were not associated with changes in EGFR expression or activity, suggesting that cholesterol regulates this signaling pathway downstream of EGFR. We conclude that alterations in membrane lipid domain signaling resulting from reduced cholesterol content facilitate enhanced depolarization- and EGF-induced pulmonary vasoconstriction after CH.

Mechanisms and regulation of cholesterol homeostasis.

Cholesterol homeostasis is vital for proper cellular and systemic functions. Disturbed cholesterol balance underlies not only cardiovascular disease but also an increasing number of other diseases such as neurodegenerative diseases and cancers. The cellular cholesterol level reflects the dynamic balance between biosynthesis, uptake, export and esterification - a process in which cholesterol is converted to neutral cholesteryl esters either for storage in lipid droplets or for secretion as constituents of lipoproteins. In this Review, we discuss the latest advances regarding how each of the four parts of cholesterol metabolism is executed and regulated. The key factors governing these pathways and the major mechanisms by which they respond to varying sterol levels are described. Finally, we discuss how these pathways function in a concerted manner to maintain cholesterol homeostasis.

Antibody-induced crosslinking and cholesterol-sensitive, anomalous diffusion of nicotinic acetylcholine receptors.

Synaptic strength depends on the number of cell-surface neurotransmitter receptors in dynamic equilibrium with intracellular pools. Dysregulation of this homeostatic balance occurs, for example in myasthenia gravis, an autoimmune disease characterized by a decrease in the number of postsynaptic nicotinic acetylcholine receptors (nAChRs). Monoclonal antibody mAb35 mimics this effect. Here we use STORM nanoscopy to characterize the individual and ensemble dynamics of monoclonal antibody-crosslinked receptors in the clonal cell line CHO-K1/A5, which robustly expresses adult muscle-type nAChRs. Antibody labeling of live cells results in 80% receptor immobilization. The remaining mobile fraction exhibits a heterogeneous combination of Brownian and anomalous diffusion. Single-molecule trajectories exhibit a two-state switching behavior between free Brownian walks and anticorrelated walks within confinement areas. The latter act as permeable fences (~34 nm radius, ~400 ms lifetime). Dynamic clustering, trapping, and immobilization also occur in larger nanocluster zones (120-180 nm radius) with longer lifetimes (11 ± 1 s), in a strongly cholesterol-sensitive manner. Cholesterol depletion increases the size of the clustering phenomenon; cholesterol enrichment has the opposite effect. The disclosed high proportion of monoclonal antibody-crosslinked immobile receptors, together with their anomalous, cholesterol-sensitive diffusion and clustering, provides new insights into the antibody-enhanced antigenic modulation that leads to physiopathological internalization and degradation of receptors in myasthenia.

Cholesterol alters the inhibitory efficiency of peptide-based membrane fusion inhibitor.

The membrane composition modulates membrane fusion by altering membrane physical properties and the structure, organization and dynamics of fusion proteins and peptides. The journey of developing peptide-based viral fusion inhibitors is often stalled by the change in lipid composition of viral and target membranes. This makes it important to study the role of membrane composition on the organization, dynamics and fusion inhibiting abilities of the peptide-based fusion inhibitors. Cholesterol, an important constituent of mammalian cell membrane, modulates bilayer properties in multiple ways and impart its effect on the membrane fusion. We have previously shown that TG-23 peptide derived from phagosomal coat protein, coronin 1, shows significant inhibition of fusion between membranes without cholesterol. In this work, we have studied the effect of the TG-23 peptide on the polyethylene glycol-mediated membrane fusion in presence of different concentrations of membrane cholesterol. Our results show that the inhibitory effect of TG-23 is being completely reversed in cholesterol containing membranes. We have evaluated the structure, organization, dynamics and depth of penetration of TG-23 in membranes having different lipid compositions and its effect on membrane properties. Our results demonstrate that cholesterol does not affect the secondary structure of the peptide, however, alters the depth of penetration of the peptide and modifies peptide organization and dynamics. The cholesterol dependent change in organization and dynamics of the peptide influences its efficacy in membrane fusion. Therefore, we envisage that the study of peptide organization and dynamics is extremely important to determine the effect of peptide on the membrane fusion.

Cholesterol Trafficking: An Emerging Therapeutic Target for Angiogenesis and Cancer.

Cholesterol is an essential structural component of cellular membranes. In addition to the structural role, it also serves as a precursor to a variety of steroid hormones and has diverse functions in intracellular signal transduction. As one of its functions in cell signaling, recent evidence suggests that cholesterol plays a key role in regulating angiogenesis. This review discusses the role of cholesterol in angiogenesis, with a particular emphasis on cholesterol trafficking in endothelial cell signaling. Small molecule inhibitors of cholesterol trafficking and their preclinical and clinical development targeting angiogenesis and cancer are also discussed.

Caveolins; An Assailant or An Ally of Various Cellular Disorders.

Caveolae have impressive morphological highlights of the cytomembrane of mammalian cells which involve in wide diversity of cellular functions involving signaling pathways and cholesterol hastening. Caveolin proteins possess a 'scaffolding' domain which for caveolin-1 and caveolin-3 appear to act a dominant role in signal regulation through caveolae. Caveolin-1 is treated to be protein in the cytomembrane entrapped with caveolae in endothelial cells and vascular smooth muscle cells which diminish nitric oxide (NO) by fill up the calcium/calmodulin (Ca2+/CaM) confining point of endothelial nitric oxide synthase (eNOS), decrease NO generation produce endothelial dysfunction and atherosclerotic injury development. It is a cholesterol-binding layer protein associated with cell cholesterol transport and also shows cardioprotective action through ischemic preconditioning (IPC) in diabetic and postmenopausal rat heart. Additionally it is ensnared in the procedures of tumorigenesis, prostate disease, and inflammation. The present study in the paper is to explore the structural functionalities of caveolins and their contributory role in CVS disorders and various other diseases.

Effects of coconut oil associated with a physical exercises program on body composition and lipid profile / Efeitos do óleo de coco associado com um programa de exercícios físicos sobre a composição corporal e perfil lipídico

ABSTRACT The aim of this study was to evalute the effects of supplementation of coconut oil associated with a physical exercise program on body composition and lipid profile in normolipid eutrophic women. The sample was composed of 20 women randomized divided into two groups, supplemented exercise group with 13 mL/day of coconut oil (GES, n= 10) and unsuppemented exercie group with coconut oil (GEU), n= 10). Perimeters measurements of central adiposity, fat (%), fat mass, lean mass, total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c) and triglycerides concentrations were evaluated in the beginning and in the final of 12 weeks of intervention. For intragroup and intergroup comparisons was used dependentes and independentes sample t-test. The results showed that 12 weeks of intervention modified the central adiposity in the GES group, decreased 2,6% the waist cincunference compared to GEU group (p<0.05). The fat (%), fat mass and lean mass did not change after 12 weeks of intervention between GES and GEU groups (p>0.05). In the comparation of lipid profile between groups, GES group decreased 3% the LDL-c while the GEU group increased 13.7% the total cholesterol and 14.2% the LDL-c concentration (p<0.05). In conclusion, coconut oil associated with a physical exercise program did not modify the body composition and attenuate the changes in the lipid profile in normolipid eutrophic women.

RESUMO O objetivo deste estudo foi avaliar os efeitos da suplementação de óleo de coco associado com um programa de exercícios físicos sobre a composição corporal e perfil lipídico em mulheres eutróficas normolipidicas. A amostra foi composta de 20 mulheres divididas aleatoriamente em 2 grupos, grupo exercício suplementado com 13 mL/dia de óleo de coco (GCO; n=10) e grupo exercício não suplementado com óleo de coco (GSO; n=10). Foram avaliados medidas perimétricas de adiposidade central, gordura (%), massa gorda, massa magra, níveis séricos de colesterol total, LDL-c, HDL-c e triglicérides no início e no final de 12 semanas de intervenção. Para as comparações intragrupos e entre os grupos foi utilizado o teste T para amostras dependentes e independentes. Os resultados mostraram que 12 semanas de intervenção modificou a adiposidade central no grupo GCO, diminuindo 2,6% a circunferência da cintura comparado ao grupo GSO (p<0,05). A gordura (%), massa gorda e massa magra não se modificaram após 12 semanas de intervenção nos grupos GCO e GSO (p<0,05). Na comparação do perfil lipídico entre os grupos, o grupo GCO diminui 3% o LDL-c enquanto que o grupo GSO aumentou 13,7% o colesterol total e 14,2% o LDL-c (p<0,05). Em conclusão, o óleo de coco associado com um programa de exercício físico aeróbico não modifica a composição corporal e atenua as alterações no perfil lipídico em mulheres eutróficas normolipidicas.

The role of cholesterol oxidation products in food toxicity.

Food consumption can lead to the accumulation of certain chemical compounds able to exert toxic activities against humans. Of mayor interests are those molecules generated during food processing and handling, since their occurrence and distribution depend of many intrinsic and extrinsic factors. Cholesterol - a lipid constituent of mammalian cells - is the precursor of several toxic molecules known as cholesterol oxidation products (COPs). In the last decades, it has been demonstrated that food processing can dramatically trigger COPs accumulation in meats, eggs, dairy products, fish and poultry. On the other hand, countless scientific evidences have pointed out the highly toxic and pathogenic activities of COPs, from cancer stimulation to neurodegenerative disorders, via molecular mechanisms that are largely unexplored. The aim of this review is to merge the evidence on COPs accumulation in foods and their toxic activities through dietary intake, as from in vivo and in vitro studies. We consider that it is imperative to systematically monitor the formation of COPs to bridge these quantitative efforts with a risk exposure assessment on sensitive populations.

Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation.

Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos-expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.

Sterol Binding by the Tombusviral Replication Proteins Is Essential for Replication in Yeast and Plants.

Membranous structures derived from various organelles are important for replication of plus-stranded RNA viruses. Although the important roles of co-opted host proteins in RNA virus replication have been appreciated for a decade, the equally important functions of cellular lipids in virus replication have been gaining full attention only recently. Previous work with Tomato bushy stunt tombusvirus (TBSV) in model host yeast has revealed essential roles for phosphatidylethanolamine and sterols in viral replication. To further our understanding of the role of sterols in tombusvirus replication, in this work we showed that the TBSV p33 and p92 replication proteins could bind to sterols in vitro The sterol binding by p33 is supported by cholesterol recognition/interaction amino acid consensus (CRAC) and CARC-like sequences within the two transmembrane domains of p33. Mutagenesis of the critical Y amino acids within the CRAC and CARC sequences blocked TBSV replication in yeast and plant cells. We also showed the enrichment of sterols in the detergent-resistant membrane (DRM) fractions obtained from yeast and plant cells replicating TBSV. The DRMs could support viral RNA synthesis on both the endogenous and exogenous templates. A lipidomic approach showed the lack of enhancement of sterol levels in yeast and plant cells replicating TBSV. The data support the notion that the TBSV replication proteins are associated with sterol-rich detergent-resistant membranes in yeast and plant cells. Together, the results obtained in this study and the previously published results support the local enrichment of sterols around the viral replication proteins that is critical for TBSV replication.IMPORTANCE One intriguing aspect of viral infections is their dependence on efficient subcellular assembly platforms serving replication, virion assembly, or virus egress via budding out of infected cells. These assembly platforms might involve sterol-rich membrane microdomains, which are heterogeneous and highly dynamic nanoscale structures usurped by various viruses. Here, we demonstrate that TBSV p33 and p92 replication proteins can bind to sterol in vitro Mutagenesis analysis of p33 within the CRAC and CARC sequences involved in sterol binding shows the important connection between the abilities of p33 to bind to sterol and to support TBSV replication in yeast and plant cells. Together, the results further strengthen the model that cellular sterols are essential as proviral lipids during viral replication.

[Cholesterol metabolism and non-alcoholic steatohepatitis].

The disease spectrum of non-alcoholic fatty liver disease (NAFLD) includes non-alcoholic simple fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), as well as liver cirrhosis and hepatocellular carcinoma, with the most serious type being NASH. The morbidity of NAFLD is seeing an increase year by year in the world, and it is a common cause of chronic hepatic disease and lacks effective treatment. The pathogenesis of NASH is still unknown, and the "two-hit" hypothesis was used to explain the mechanism of NASH. Recent research has found that cholesterol metabolism is closely related to the pathogenesis and severity of NASH. The validity of the "two-hit" hypothesis has been recently challenged, which gives rise to "multi-parallel hit" hypothesis. Cholesterol affects membrane fluidity and membrane protein function through genetic factors, and it can also induce unfolded protein response, and generate toxic oxysterol. Free cholesterol can activate hepatic Kupffer and stellate cells to produce inflammatory cytokines and collagen. The formation of cholesterol crystallization and crown-like structures can damage liver cells and activate Kupffer cells. The above processes can all aggravate liver damage, thus accelerating the development and making the clinical manifestations of NASH even worse. In the present review we summarize the association between cholesterol metabolism and pathogenesis of NASH.

Common molecular mechanism of amyloid pore formation by Alzheimer's ß-amyloid peptide and α-synuclein.

Calcium-permeable pores formed by small oligomers of amyloid proteins are the primary pathologic species in Alzheimer's and Parkinson's diseases. However, the molecular mechanisms underlying the assembly of these toxic oligomers in the plasma membrane of brain cells remain unclear. Here we have analyzed and compared the pore-forming capability of a large panel of amyloid proteins including wild-type, variant and truncated forms, as well as synthetic peptides derived from specific domains of Aß1-42 and α-synuclein. We show that amyloid pore formation involves two membrane lipids, ganglioside and cholesterol, that physically interact with amyloid proteins through specific structural motifs. Mutation or deletion of these motifs abolished pore formation. Moreover, α-synuclein (Parkinson) and Aß peptide (Alzheimer) did no longer form Ca(2+)-permeable pores in presence of drugs that target either cholesterol or ganglioside or both membrane lipids. These results indicate that gangliosides and cholesterol cooperate to favor the formation of amyloid pores through a common molecular mechanism that can be jammed at two different steps, suggesting the possibility of a universal therapeutic approach for neurodegenerative diseases. Finally we present the first successful evaluation of such a new therapeutic approach (coined "membrane therapy") targeting amyloid pores formed by Aß1-42 and α-synuclein.

Colesterol y aterosclerosis. Consideraciones históricas y tratamiento / Cholesterol and atherosclerosis. Historical considerations and treatment

Resumen El colesterol es un esteroide precursor de hormonas, componente esencial de la membrana celular, sin embargo, alteraciones en la regulación de la síntesis, absorción y excreción del colesterol predisponen al desarrollo de enfermedades cardiovasculares de origen aterosclerótico. De esta manera, reconociendo los acontecimientos históricos desde hace 200 años, con Michel Chevreul que le dio el nombre "colesterina", más tarde Lobstein que acuñó el término aterosclerosis y Marchand que lo introduce, Anichkov que identifica el colesterol en las placas de ateroma, y el descubrimiento del receptor LDL por Brown y Goldstein; además de la aparición de los diferentes fármacos que han surgido desde los fibratos, las estatinas y en esta década cetrapibs, muy prometedores para aumentar el HDL, en forma más reciente, ezetimibe y anti-PCSK9 para inhibir el proceso de degradación del receptor LDL; no obstante, estos avances no han sido suficientes para disminuir la morbilidad en enfermedades cardiovasculares.

Abstract Cholesterol is a precursor of steroid hormones and an essential component of the cell membrane, however, altered regulation of the synthesis, absorption and excretion of cholesterol predispose to cardiovascular diseases of atherosclerotic origin. Despite, the recognition of historical events for 200 years, starting with Michel Chevreul naming "cholesterol"; later on, Lobstein coining the term atherosclerosis and Marchand introducing it, Anichkov identifying cholesterol in atheromatous plaque, and Brown and Goldstein discovering LDL receptor; as well as the emerging of different drugs, such as fibrates, statins and cetrapibs this decade, promising to increase HDL and the most recent ezetimibe and anti-PCSK9 to inhibit the degradation of LDL receptor, however morbidity has not been reduced in cardiovascular disease.

Ligand Activation of ERRα by Cholesterol Mediates Statin and Bisphosphonate Effects.

Nuclear receptors (NRs) are key regulators of gene expression and physiology. Nearly half of all human NRs lack endogenous ligands including estrogen-related receptor α (ERRα). ERRα has important roles in cancer, metabolism, and skeletal homeostasis. Affinity chromatography of tissue lipidomes with the ERRα ligand-binding domain (LBD) and subsequent transcriptional assays identified cholesterol as an endogenous ERRα agonist. Perturbation of cholesterol biosynthesis or inhibition of ERRα revealed the interdependence of cholesterol and ERRα. In bone, the effects of cholesterol, statin, and bisphosphonate on osteoclastogenesis require ERRα; and consequently, cholesterol-induced bone loss or bisphosphonate osteoprotection is lost in ERRα knockout mice. Furthermore, statin induction of muscle toxicity and cholesterol suppression of macrophage cytokine secretion are impaired by loss or inhibition of ERRα. These findings reveal a key step in ERRα regulation and explain the actions of two highly prescribed drugs, statins and bisphosphonates.

The Role of Cholesterol in the Pathogenesis of NASH.

Lipotoxicity drives the development of progressive hepatic inflammation and fibrosis in a subgroup of patients with nonalcoholic fatty liver disease (NAFLD), causing nonalcoholic steatohepatitis (NASH) and even progression to cirrhosis and hepatocellular carcinoma (HCC). While the underlying molecular mechanisms responsible for the development of inflammation and fibrosis that characterize progressive NASH remain unclear, emerging evidence now suggests that hepatic free cholesterol (FC) is a major lipotoxic molecule critical in the development of experimental and human NASH. In this review, we examine the effects of excess FC in hepatocytes, Kupffer cells (KCs), and hepatic stellate cells (HSCs), and the subcellular mechanisms by which excess FC can induce cellular toxicity or proinflammatory and profibrotic effects in these cells.

Neuroprotective effects of estrogens: the role of cholesterol.

INTRODUCTION: Experimental and clinical evidence suggests that estrogens have protective effects in the brain. Nevertheless, their potential role against neurodegenerative diseases, in particular Alzheimer's disease (AD), is still a matter of debate. The identification of the seladin-1 gene (for SELective Alzheimer's Disease INdicator-1), which appeared to be significantly less expressed in brain region affected in AD, opened a new scenario in the field of neuroprotective mechanisms. Seladin-1 was found to have neuroprotective properties through its anti-apoptotic activity. In addition, it was subsequently demonstrated that seladin-1 also has enzymatic activity, because it catalyzes the conversion of desmosterol into cholesterol. Several studies have shown that an appropriate amount of membrane cholesterol plays a pivotal role to protect nerve cells against ß-amyloid toxicity in AD and to counteract the synthesis of ß-amyloid. METHODS AND RESULTS: We demonstrated that the expression of seladin-1, as well as the synthesis of cell cholesterol, is stimulated by estrogens in human neuronal precursor cells. Cholesterol enriched cells became more resistant against oxidative stress and ß-amyloid toxicity. We thus hypothesized that seladin-1 might be a mediator of the neuroprotective effects of estrogens. Indeed, in cells in which seladin-1 gene expression had been silenced by siRNA the protective effects of estrogens were lost. This finding indicates that seladin-1 is a crucial mediator of the neuroprotective effects of these hormones, at least in our cell model. CONCLUSIONS: In summary, these results establish a new link between estrogens and cholesterol, which is represented by the neuroprotective factor seladin-1.