Modulation of the Cellular microRNA Landscape: Contribution to the Protective Effects of High-Density Lipoproteins (HDL).

High-density lipoproteins (HDL) play an established role in protecting against cellular dysfunction in a variety of different disease contexts; however, harnessing this therapeutic potential has proved challenging due to the heterogeneous and relative instability of this lipoprotein and its variable cargo molecules. The purpose of this study is to examine the contribution of microRNA (miRNA; miR) sequences, either delivered directly or modulated endogenously, to these protective functions. This narrative review introduces the complex cargo carried by HDL, the protective functions associated with this lipoprotein, and the factors governing biogenesis, export and the uptake of microRNA. The possible mechanisms by which HDL can modulate the cellular miRNA landscape are considered, and the impact of key sequences modified by HDL is explored in diseases such as inflammation and immunity, wound healing, angiogenesis, dyslipidaemia, atherosclerosis and coronary heart disease, potentially offering new routes for therapeutic intervention.

Program to Enhance Adjustment to Residential Living (PEARL): Effect on Adjustment, Anxiety, Quality of Life, and Stress.

OBJECTIVES: The Program to Enhance Adjustment to Residential Living (PEARL) is a five session intervention primarily designed to address high rates of depression in newly admitted residents. This study reports the efficacy of PEARL on secondary outcomes of resident adjustment, symptoms of anxiety, quality of life, and stress. METHODS: A cluster randomized controlled trial was conducted with 219 newly admitted nursing home residents (M age = 85.5 years) from 42 nursing homes. Outcomes were assessed at baseline, post-intervention, and at two and six month post-intervention follow-up, compared to a standard care condition. RESULTS: There was a significant overall condition by time interaction for adjustment (p = .027) and quality of life (p = .015), but not for stress (p = .309). While the overall condition by time interaction was not significant for anxiety (p = .221), there was a significant interaction contrast six-month post-intervention, indicating a greater decrease in anxiety scores in the intervention group relative to control (p = .039). CONCLUSIONS: This study demonstrates the broad effects of PEARL on the wellbeing of newly admitted residents. CLINICAL IMPLICATIONS: PEARL is a brief intervention that may be feasible for routine use in nursing homes to facilitate adjustment and improve residents' quality of life.

Transmembrane stem cell factor protein therapeutics enhance revascularization in ischemia without mast cell activation.

Stem cell factor (SCF) is a cytokine that regulates hematopoiesis and other biological processes. While clinical treatments using SCF would be highly beneficial, these have been limited by toxicity related to mast cell activation. Transmembrane SCF (tmSCF) has differential activity from soluble SCF and has not been explored as a therapeutic agent. We created novel therapeutics using tmSCF embedded in proteoliposomes or lipid nanodiscs. Mouse models of anaphylaxis and ischemia revealed the tmSCF-based therapies did not activate mast cells and improved the revascularization in the ischemic hind limb. Proteoliposomal tmSCF preferentially acted on endothelial cells to induce angiogenesis while tmSCF nanodiscs had greater activity in inducing stem cell mobilization and recruitment to the site of injury. The type of lipid nanocarrier used altered the relative cellular uptake pathways and signaling in a cell type dependent manner. Overall, we found that tmSCF-based therapies can provide therapeutic benefits without off target effects.

Homo Sapiens (Hsa)-microRNA (miR)-6727-5p Contributes to the Impact of High-Density Lipoproteins on Fibroblast Wound Healing In Vitro.

Chronic, non-healing wounds are a significant cause of global morbidity and mortality, and strategies to improve delayed wound closure represent an unmet clinical need. High-density lipoproteins (HDL) can enhance wound healing, but exploitation of this finding is challenging due to the complexity and instability of these heterogeneous lipoproteins. The responsiveness of primary human neonatal keratinocytes, and neonatal and human dermal fibroblasts (HDF) to HDL was confirmed by cholesterol efflux, but promotion of 'scrape' wound healing occurred only in primary human neonatal (HDFn) and adult fibroblasts (HDFa). Treatment of human fibroblasts with HDL induced multiple changes in the expression of small non-coding microRNA sequences, determined by microchip array, including hsa-miR-6727-5p. Intriguingly, levels of hsa-miR-6727-5p increased in HDFn, but decreased in HDFa, after exposure to HDL. Delivery of a hsa-miR-6727-5p mimic elicited repression of different target genes in HDFn (ZNF584) and HDFa (EDEM3, KRAS), and promoted wound closure in HDFn. By contrast, a hsa-miR-6727-5p inhibitor promoted wound closure in HDFa. We conclude that HDL treatment exerts distinct effects on the expression of hsa-miR-6727-5p in neonatal and adult fibroblasts, and that this is a sequence which plays differential roles in wound healing in these cell types, but cannot replicate the myriad effects of HDL.

Trajectory and Predictors of Mental Health Symptoms and Wellbeing in Newly Admitted Nursing Home Residents.

OBJECTIVES: This study determined changes in multiple aspects of mental health and wellbeing in newly admitted nursing home residents, and identified risk and protective factors. METHODS: Participants were 204 residents recently admitted to one of 42 nursing homes in Melbourne, Australia. A subgroup of 82 participants were followed up eight months post-admission. Depression, anxiety, stress, adjustment, and quality of life were assessed at baseline and follow-up. Predictive factors (demographics, health, transition factors, nursing home characteristics) were examined in multiple regression analyses. RESULTS: Rates of depression and anxiety were high at both baseline and follow-up. Low self-rated health and medical comorbidity predicted poor wellbeing at baseline. Higher perceived control in the relocation to the nursing home and engagement in meaningful activities were associated with better post-admission outcomes. Baseline psychotropic medication use predicted lower anxiety at follow-up but did not impact depressive symptoms. CONCLUSIONS: There were no significant changes in mental health and wellbeing from one to eight months post-admission. The negative effect of residing in a for-profit nursing home requires further investigation. CLINICAL IMPLICATIONS: Individual activity scheduling and an opportunity to participate in relocation decision-making and planning may support resident wellbeing post-admission.

Induction of microRNA hsa-let-7d-5p, and repression of HMGA2, contribute protection against lipid accumulation in macrophage 'foam' cells.

Accumulation of excess cholesterol and cholesteryl ester in macrophage 'foam' cells within the arterial intima characterises early 'fatty streak' atherosclerotic lesions, and is accompanied by epigenetic changes, including altered expression of microRNA sequences which determine of gene and protein expression. This study established that exposure to lipoproteins, including acetylated LDL, induced macrophage expression of microRNA hsa-let-7d-5p, a sequence previously linked with tumour suppression, and repressed expression of one of its target genes, high mobility group AT hook 2 (HMGA2). A let-7d-5p mimic repressed expression of HMGA2 (18%; p < 0.05) while a marked increase (2.9-fold; p < 0.05) in expression of HMGA2 was noted in the presence of let-7d-5p inhibitor. Under these conditions, let-7d-5p mimic significantly (p < 0.05) decreased total (10%), free (8%) and cholesteryl ester (21%) mass, while the inhibitor significantly (p < 0.05) increased total (29%) and free cholesterol (29%) mass, compared with the relevant controls. Let-7d-5p inhibition significantly (p < 0.05) increased endogenous biosynthesis of cholesterol (38%) and cholesteryl ester (39%) pools in macrophage 'foam' cells, without altering the cholesterol efflux pathway, or esterification of exogenous radiolabelled oleate. Let-7d-5p inhibition in sterol-loaded cells increased the level of HMGA2 protein (32%; p < 0.05), while SiRNA knockdown of this protein (29%; p < 0.05) resulted in a (21%, p < 0.05) reduction in free cholesterol mass. Thus, induction of let-7d-5p, and repression of its target HMGA2, in macrophages is a protective response to the challenge of increased cholesterol influx into these cells; dysregulation of this response may contribute to atherosclerosis and other disorders such as cancer.

MicroRNA Sequences Modulated by Beta Cell Lipid Metabolism: Implications for Type 2 Diabetes Mellitus.

Alterations in lipid metabolism within beta cells and islets contributes to dysfunction and apoptosis of beta cells, leading to loss of insulin secretion and the onset of type 2 diabetes. Over the last decade, there has been an explosion of interest in understanding the landscape of gene expression which influences beta cell function, including the importance of small non-coding microRNA sequences in this context. This review sought to identify the microRNA sequences regulated by metabolic challenges in beta cells and islets, their targets, highlight their function and assess their possible relevance as biomarkers of disease progression in diabetic individuals. Predictive analysis was used to explore networks of genes targeted by these microRNA sequences, which may offer new therapeutic strategies to protect beta cell function and delay the onset of type 2 diabetes.

Protection against Glucolipotoxicity by High Density Lipoprotein in Human PANC-1 Hybrid 1.1B4 Pancreatic Beta Cells: The Role of microRNA.

High-density lipoproteins provide protection against the damaging effects of glucolipotoxicity in beta cells, a factor which sustains insulin secretion and staves off onset of type 2 diabetes mellitus. This study examines epigenetic changes in small non-coding microRNA sequences induced by high density lipoproteins in a human hybrid beta cell model, and tests the impact of delivery of a single sequence in protecting against glucolipotoxicity. Human PANC-1.1B4 cells were used to establish Bmax and Kd for [3H]cholesterol efflux to high density lipoprotein, and minimum concentrations required to protect cell viability and reduce apoptosis to 30mM glucose and 0.25 mM palmitic acid. Microchip array identified the microRNA signature associated with high density lipoprotein treatment, and one sequence, hsa-miR-21-5p, modulated via delivery of a mimic and inhibitor. The results confirm that low concentrations of high-density lipoprotein can protect against glucolipotoxicity, and report the global microRNA profile associated with this lipoprotein; delivery of miR-21-5p mimic altered gene targets, similar to high density lipoprotein, but could not provide sufficient protection against glucolipotoxicity. We conclude that the complex profile of microRNA changes due to HDL treatment may be difficult to replicate using a single microRNA, findings which may inform current drug strategies focused on this approach.

The effectiveness of the Program to Enhance Adjustment to Residential Living (PEARL) in reducing depression in newly admitted nursing home residents.

BACKGROUND: Depression is common in nursing homes, particularly among newly admitted residents. This cluster randomised controlled trial evaluated the effectiveness of the Program to Enhance Adjustment to Residential Living (PEARL) in reducing depression in this group. METHODS: Participants were 219 newly-admitted residents (mean of 4.4 weeks since admission) in 42 nursing homes in Melbourne, Australia, with a mean age of 85.5 years (SD = 7.3). Nursing homes were randomly allocated to the intervention or standard care condition. Level of depressive symptoms was evaluated at baseline (T1), one week post- intervention (T2), 2 months post-intervention (T3, primary end point), and 6 months post-intervention (T4). Changes in depressive symptoms in the intervention and control groups over time were compared using a multilevel model, with nursing homes modelled as random intercept. RESULTS: In intention to treat analyses, depressive symptoms reduced from T1 to T3 to a greater degree in the intervention condition (Mchange=2.56, SDchange=5.71) than in the control (Mchange=0.63, SDchange=5.25), with a significant, small-medium treatment effect size (p=.035; Cohen's d=0.36). The reduction in depressive symptoms from T1 to T4 was not significant (p=.369; Cohen's d=0.32). LIMITATIONS: The findings require replication, particularly comparing PEARL with an active control condition. CONCLUSIONS: PEARL is a simple, brief program that was effective in reducing symptoms of depression in newly admitted nursing home residents.

MicroRNA sequences modulating inflammation and lipid accumulation in macrophage "foam" cells: Implications for atherosclerosis.

Accumulation of macrophage "foam" cells, laden with cholesterol and cholesteryl ester, within the intima of large arteries, is a hallmark of early "fatty streak" lesions which can progress to complex, multicellular atheromatous plaques, involving lipoproteins from the bloodstream and cells of the innate and adaptive immune response. Sterol accumulation triggers induction of genes encoding proteins mediating the atheroprotective cholesterol efflux pathway. Within the arterial intima, however, this mechanism is overwhelmed, leading to distinct changes in macrophage phenotype and inflammatory status. Over the last decade marked gains have been made in understanding of the epigenetic landscape which influence macrophage function, and in particular the importance of small non-coding micro-RNA (miRNA) sequences in this context. This review identifies some of the miRNA sequences which play a key role in regulating "foam" cell formation and atherogenesis, highlighting sequences involved in cholesterol accumulation, those influencing inflammation in sterol-loaded cells, and novel sequences and pathways which may offer new strategies to influence macrophage function within atherosclerotic lesions.

Genome wide analysis of gene expression changes in skin from patients with type 2 diabetes.

Non-healing chronic ulcers are a serious complication of diabetes and are a major healthcare problem. While a host of treatments have been explored to heal or prevent these ulcers from forming, these treatments have not been found to be consistently effective in clinical trials. An understanding of the changes in gene expression in the skin of diabetic patients may provide insight into the processes and mechanisms that precede the formation of non-healing ulcers. In this study, we investigated genome wide changes in gene expression in skin between patients with type 2 diabetes and non-diabetic patients using next generation sequencing. We compared the gene expression in skin samples taken from 27 patients (13 with type 2 diabetes and 14 non-diabetic). This information may be useful in identifying the causal factors and potential therapeutic targets for the prevention and treatment of diabetic related diseases.

Gypenosides mediate cholesterol efflux and suppress oxidized LDL induced inflammation in retinal pigment epithelium cells.

Age-related macular degeneration (AMD) is a predominant cause of visual deficit in aged population. Abnormal accumulation of cholesterol, including oxidized low-density lipoprotein (oxLDL), underneath the retinal pigment epithelium (RPE) cells contributes to the development of AMD. Gypenosides (Gyp) are glycosides extracted from Gynostemma pentaphyllum and have demonstrated protective effects against inflammation and oxidative stress. To determine the therapeutic potential of Gyp for AMD, we investigated its effect on cholesterol trafficking and metabolism and assessed the protective function of Gyp against oxLDL-induced damage in RPE cells. Cholesterol efflux to high-density lipoprotein (HDL) and human serum was significantly increased in RPE cells treated with Gyp when compared to untreated control cells. Expression of cholesterol metabolism (CYP27A1, CYP46A1) and trafficking (TSPO, ABCA1 and ABCG1) genes was also markedly increased in Gyp-treated RPE cells. OxLDL-treated RPE cells had significantly increased cholesterol accumulation and lipid droplet formation. There were marked increases in reactive oxygen species (ROS) generation and proinflammatory cytokines via NF-κB activation in RPE cells treated with oxLDL, while incubation with Gyp rectified these changes. These findings provide pharmacological evidence that Gyp has the potential to treat patients with early onset AMD by promoting cellular cholesterol removal from RPE cells and inhibiting inflammation and oxidative stress.

A feasibility and acceptability study of an adaptation of the Mindful Self-Compassion program for adult cancer patients.

OBJECTIVES: Psychosocial interventions that mitigate psychosocial distress in cancer patients are important. The primary aim of this study was to examine the feasibility and acceptability of an adaptation of the Mindful Self-Compassion (MSC) program among adult cancer patients. A secondary aim was to examine pre-post-program changes in psychosocial wellbeing. METHOD: The research design was a feasibility and acceptability study, with an examination of pre- to post-intervention changes in psychosocial measures. A study information pack was posted to 173 adult cancer patients 6 months-5 years post-diagnosis, with an invitation to attend an eight-week group-based adaptation of the MSC program. RESULTS: Thirty-two (19%) consented to the program, with 30 commencing. Twenty-seven completed the program (mean age: 62.93 years, SD 14.04; 17 [63%] female), attending a mean 6.93 (SD 1.11) group sessions. There were no significant differences in medico-demographic factors between program-completers and those who did not consent. However, there was a trend toward shorter time since diagnosis in the program-completers group. Program-completers rated the program highly regarding content, relevance to the concerns of cancer patients, and the likelihood of recommending the program to other cancer patients. Sixty-three percent perceived that their mental wellbeing had improved from pre- to post-program; none perceived a deterioration in mental wellbeing. Small-to-medium effects were observed for depressive symptoms, fear of cancer recurrence, stress, loneliness, body image satisfaction, mindfulness, and self-compassion. SIGNIFICANCE OF RESULTS: The MSC program appears feasible and acceptable to adults diagnosed with non-advanced cancer. The preliminary estimates of effect sizes in this sample suggest that participation in the program was associated with improvements in psychosocial wellbeing. Collectively, these findings suggest that there may be value in conducting an adequately powered randomized controlled trial to determine the efficacy of the MSC program in enhancing the psychosocial wellbeing of cancer patients.

Genetic obesity increases pancreatic expression of mitochondrial proteins which regulate cholesterol efflux in BRIN-BD11 insulinoma cells.

Pancreatic ß-cells are sensitive to fluctuations in cholesterol content, which can damage the insulin secretion pathway, contributing to the aetiology of type 2 diabetes mellitus. Cholesterol efflux to (apo)lipoproteins, via ATP-binding cassette (ABC) transporter A1 (ABCA1), can prevent intracellular cholesterol accumulation; in some peripheral cells, ABCA1-dependent efflux is enhanced by promotion of cholesterol trafficking to, and generation of Liver X receptor (LXR) ligands by, mitochondrial sterol 27-hydroxylase (Cyp27A1 (cytochrome P450 27 A1/sterol 27-hydroxylase)) and its redox partners, adrenodoxin (ADX) and ADX reductase (ADXR). Despite this, the roles of mitochondrial cholesterol trafficking (steroidogenic acute regulatory protein [StAR] and 18-kDa translocator protein [TSPO]) and metabolising proteins in insulin-secreting cells remain wholly uncharacterised. Here, we demonstrate an increase in pancreatic expression of Cyp27A1, ADXR, TSPO and LXRα, but not ADX or StAR, in obese (fa/fa) rodents compared with lean (Fa/?) controls. Overexpression of Cyp27A1 alone in BRIN-BD11 cells increased INS2 expression, without affecting lipid metabolism; however, after exposure to low-density lipoprotein (LDL), cholesterol efflux to (apo)lipoprotein acceptors was enhanced in Cyp27A1-overexpressing cells. Co-transfection of Cyp27A1, ADX and ADXR, at a ratio approximating that in pancreatic tissue, stimulated cholesterol efflux to apolipoprotein A-I (apoA-I) in both basal and cholesterol-loaded cells; insulin release was stimulated equally by all acceptors in cholesterol-loaded cells. Thus, genetic obesity increases pancreatic expression of Cyp27A1, ADXR, TSPO and LXRα, while modulation of Cyp27A1 and its redox partners promotes cholesterol efflux from insulin-secreting cells to acceptor (apo)lipoproteins; this response may help guard against loss of insulin secretion caused by accumulation of excess intracellular cholesterol.

Receipt and Perceived Helpfulness of Mental Illness Information: Findings from the Australian National Survey of Mental Health and Wellbeing.

The distribution of mental illness information is a crucial element of mental health promotion initiatives. We assessed the receipt and perceived helpfulness of such information in Australia. Data from the Australian National Survey of Mental Health and Wellbeing indicated that, during the year prior to the survey, 33.7% of Australians received mental illness information; of these, 51.2% found it helpful. Among people with a mental disorder, 46.1% received information; of these, 67.4% found it helpful. Non-English speakers and the socially disadvantaged were less likely to receive mental illness information. Older and less educated respondents were less likely to both receive mental illness information and find it helpful. Mental health service users were more likely to receive mental illness information perceived as helpful than those who had not accessed such services. Better targeted information interventions are required to ensure those most likely to benefit receive mental illness-related information.

The potential of human induced pluripotent stem cells for modelling diabetic wound healing in vitro.

Impaired wound healing and ulceration caused by diabetes mellitus, is a significant healthcare burden, markedly impairs quality of life for patients, and is the major cause of amputation worldwide. Current experimental approaches used to investigate the complex wound healing process often involve cultures of fibroblasts and/or keratinocytes in vitro, which can be limited in terms of complexity and capacity, or utilisation of rodent models in which the mechanisms of wound repair differ substantively from that in humans. However, advances in tissue engineering, and the discovery of strategies to reprogramme adult somatic cells to pluripotency, has led to the possibility of developing models of human skin on a large scale. Generation of induced pluripotent stem cells (iPSCs) from tissues donated by diabetic patients allows the (epi)genetic background of this disease to be studied, and the ability to differentiate iPSCs to multiple cell types found within skin may facilitate the development of more complex skin models; these advances offer key opportunities for improving modelling of wound healing in diabetes, and the development of effective therapeutics for treatment of chronic wounds.

The Connexin Mimetic Peptide Gap27 and Cx43-Knockdown Reveal Differential Roles for Connexin43 in Wound Closure Events in Skin Model Systems.

In the epidermis, remodelling of Connexin43 is a key event in wound closure. However, controversy between the role of connexin channel and non-channel functions exist. We compared the impact of SiRNA targeted to Connexin43 and the connexin mimetic peptide Gap27 on scrape wound closure rates and hemichannel signalling in adult keratinocytes (AK) and fibroblasts sourced from juvenile foreskin (JFF), human neonatal fibroblasts (HNDF) and adult dermal tissue (ADF). The impact of these agents, following 24 h exposure, on GJA1 (encoding Connexin43), Ki67 and TGF-ß1 gene expression, and Connexin43 and pSmad3 protein expression levels, were examined by qPCR and Western Blot respectively. In all cell types Gap27 (100-100 µM) attenuated hemichannel activity. In AK and JFF cells, Gap27 (100 nM-100 µM) enhanced scrape wound closure rates by ~50% but did not influence movement in HNDF or ADF cells. In both JF and AK cells, exposure to Gap27 for 24 h reduced the level of Cx43 protein expression but did not affect the level in ADF and HNDF cells. Connexin43-SiRNA enhanced scrape wound closure in all the cell types under investigation. In HDNF and ADF, Connexin43-SiRNA enhanced cell proliferation rates, with enhanced proliferation also observed following exposure of HDNF to Gap27. By contrast, in JFF and AK cells no changes in proliferation occurred. In JFF cells, Connexin43-SiRNA enhanced TGF-ß1 levels and in JFF and ADF cells both Connexin43-SiRNA and Gap27 enhanced pSmad3 protein expression levels. We conclude that Connexin43 signalling plays an important role in cell migration in keratinocytes and foreskin derived fibroblasts, however, different pathways are evoked and in dermal derived adult and neonatal fibroblasts, inhibition of Connexin43 signalling plays a more significant role in regulating cell proliferation than cell migration.

Retinal pigment epithelium cholesterol efflux mediated by the 18 kDa translocator protein, TSPO, a potential target for treating age-related macular degeneration.

Cholesterol accumulation beneath the retinal pigment epithelium (RPE) cells is supposed to contribute the pathogenesis of age-related macular degeneration (AMD). Cholesterol efflux genes (APOE and ABCA1) were identified as risk factors for AMD, although how cholesterol efflux influences accumulation of this lipid in sub-RPE deposits remains elusive. The 18 kDa translocator protein, TSPO, is a cholesterol-binding protein implicated in mitochondrial cholesterol transport. Here, we investigate the function of TSPO in cholesterol efflux from the RPE cells. We demonstrate in RPE cells that TSPO specific ligands promoted cholesterol efflux to acceptor (apo)lipoprotein and human serum, while loss of TSPO resulted in impaired cholesterol efflux. TSPO-/- RPE cells also had significantly increased production of reactive oxygen species (ROS) and upregulated expression of proinflammatory cytokines (IL-1ß and TNFα). Cholesterol (oxidized LDL) uptake and accumulation were markedly increased in TSPO-/- RPE cells. Finally, in aged RPE cells, TSPO expression was reduced and cholesterol efflux impaired. These findings provide a new pharmacological concept to treat early AMD patients by stimulating cellular cholesterol removal with TSPO specific ligands or by overexpression of TSPO in RPE cells.

Mental health service use among those with depression: an exploration using Andersen's Behavioral Model of Health Service Use.

BACKGROUND: Despite positive effects on prognosis, less than half of the people diagnosed with depression access mental health services. Knowledge of what promotes such service use is limited. There is dispute about whether the receipt of mental illness related information encourages or discourages service use among those with depression. Accurate service use models are needed to inform programs designed to facilitate service use by those who would benefit most. We examine the appropriateness of Andersen's Behavioral Model of Health Service Use in this context. METHOD: Data from 451 adults identified through the Australian National Survey of Mental Health and Wellbeing as meeting International Classification of Diseases Ten (ICD-10) criteria for depression were used. RESULTS: Confirmatory factor analysis failed to verify Andersen's model. Thus, an empirically derived service use model was developed using exploratory factor analysis and then structural equation modelling. Mental health need was the strongest predictor of service use and the model suggested the importance of social connectedness in promoting service use. Participants who had received helpful mental illness information were significantly more likely to have accessed mental health services than those who had not. LIMITATIONS: The cross-sectional design and lack of replication preclude definitive conclusions CONCLUSION: Andersen's model is a useful starting point for the exploration of service use among people with depression. It is necessary, however, to develop specific models for this population.

Intracellular cholesterol transport proteins: roles in health and disease.

Effective cholesterol homoeostasis is essential in maintaining cellular function, and this is achieved by a network of lipid-responsive nuclear transcription factors, and enzymes, receptors and transporters subject to post-transcriptional and post-translational regulation, whereas loss of these elegant, tightly regulated homoeostatic responses is integral to disease pathologies. Recent data suggest that sterol-binding sensors, exchangers and transporters contribute to regulation of cellular cholesterol homoeostasis and that genetic overexpression or deletion, or mutations, in a number of these proteins are linked with diseases, including atherosclerosis, dyslipidaemia, diabetes, congenital lipoid adrenal hyperplasia, cancer, autosomal dominant hearing loss and male infertility. This review focuses on current evidence exploring the function of members of the 'START' (steroidogenic acute regulatory protein-related lipid transfer) and 'ORP' (oxysterol-binding protein-related proteins) families of sterol-binding proteins in sterol homoeostasis in eukaryotic cells, and the evidence that they represent valid therapeutic targets to alleviate human disease.