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Sterol O -acyltransferase 1 (SOAT1) is an endoplasmic reticulum (ER) resident, multi-transmembrane enzyme that belongs to the membrane-bound O -acyltransferase (MBOAT) family. It catalyzes the esterification of cholesterol to generate cholesteryl esters for cholesterol storage. SOAT1 is a target to treat several human diseases. However, its structure and mechanism remain elusive since its discovery. Here, we report the structure of human SOAT1 (hSOAT1) determined by cryo-EM. hSOAT1 is a tetramer consisted of a dimer of dimer. The structure of hSOAT1 dimer at 3.5 Å resolution reveals that a small molecule inhibitor CI-976 binds inside the catalytic chamber and blocks the accessibility of the active site residues H460, N421 and W420. Our results pave the way for future mechanistic study and rational drug design targeting hSOAT1 and other mammalian MBOAT family members. Sterol O -acyltransferase 1 (SOAT1, also named ACAT1) is an endoplasmic reticulum resident enzyme which catalyzes the esterification of cholesterol to generate cholesteryl esters. Here, authors report cryo-EM structures of human SOAT1 which reveal the binding site of the competitive inhibitor CI-976.

Ubiquitin linkage to cysteine is an unconventional modification targeting protein for degradation. However, the physiological regulation of cysteine ubiquitylation is still mysterious. Here we found that ACAT2, a cellular enzyme converting cholesterol and fatty acid to cholesteryl esters, was ubiquitylated on Cys277 for degradation when the lipid level was low. gp78–Insigs catalysed Lys48-linked polyubiquitylation on this Cys277. A high concentration of cholesterol and fatty acid, however, induced cellular reactive oxygen species (ROS) that oxidized Cys277, resulting in ACAT2 stabilization and subsequently elevated cholesteryl esters. Furthermore, ACAT2 knockout mice were more susceptible to high-fat diet-associated insulin resistance. By contrast, expression of a constitutively stable form of ACAT2 (C277A) resulted in higher insulin sensitivity. Together, these data indicate that lipid-induced stabilization of ACAT2 ameliorates lipotoxicity from excessive cholesterol and fatty acid. This unconventional cysteine ubiquitylation of ACAT2 constitutes an important mechanism for sensing lipid-overload-induced ROS and fine-tuning lipid homeostasis. Wang et al. show that lipid-induced ROS lead to ACAT2 stabilization by oxidizing a cysteine residue, thereby preventing its ubiquitylation and ACAT2 degradation. They further show that ACAT2 stabilization improves lipotoxicity and insulin resistance.

Noise pollution is reported to be associated with diabetes, but few studies have elucidated the associations between noise frequency characteristics. We aimed to evaluate the relationships between different noise frequency components and incident hyperglycaemia. An industry-based cohort of 905 volunteers was enrolled and followed up to 2012. Octave-band frequencies of workstation noise and individual noise levels were measured in 2012 to classify subjects’ exposures retrospectively. We applied Cox regression models to estimate the relative risk (RR) of hyperglycaemia. An increased RR for hyperglycaemia of 1.80 (95% confidence interval [CI]: 1.04, 3.10) was found among subjects exposed to ≥ 85 A-weighted decibels (dBA) compared with those exposed to < 70 dBA. The high-exposure groups at frequencies of 31.5, 63, 125, 250, 500, 1000, and 2000 Hz had a significantly higher risk of hyperglycaemia (all p values < 0.050) than the low-exposure groups. A 5-dB increase in noise frequencies at 31.5, 63, 125, 250, 500 Hz, and 1000 Hz was associated with an elevated risk of hyperglycaemia (all p values < 0.050), with the highest value of 1.27 (95% CI: 1.10, 1.47) at 31.5 Hz (p = 0.001). Occupational noise exposure may be associated with an increased incidence of hyperglycaemia, with the highest risk observed at 31.5 Hz.

Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration via acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant impact from atherosclerosis. Risk factors including hypercholesterolemia and hypertension promote intracranial atherosclerotic disease and carotid artery stenosis (CAS), which disrupt cerebral blood flow and trigger ischemic strokes and VCID. Apolipoprotein E (APOE) is a cholesterol and phospholipid carrier present in plasma and various tissues. APOE is implicated in dyslipidemia and Alzheimer disease (AD); however, its connection with VCID is less understood. Few experimental models for VCID exist, so much of the present information has been drawn from clinical studies. Here, we review the literature with a focus on the clinical aspects of atherosclerotic cerebrovascular disease and build a working model for the pathogenesis of VCID. We describe potential intermediate steps in this model, linking cholesterol, atherosclerosis, and APOE with VCID. APOE4 is a minor isoform of APOE that promotes lipid dyshomeostasis in astrocytes and microglia, leading to chronic neuroinflammation. APOE4 disturbs lipid homeostasis in macrophages and smooth muscle cells, thus exacerbating systemic inflammation and promoting atherosclerotic plaque formation. Additionally, APOE4 may contribute to stromal activation of endothelial cells and pericytes that disturb the blood-brain barrier (BBB). These and other risk factors together lead to chronic inflammation, atherosclerosis, VCID, and neurodegeneration. Finally, we discuss potential cholesterol metabolism based approaches for future VCID treatment.

Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-β, one of the pathological hallmarks of Alzheimer disease (AD). Acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear. Here we show that ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1-) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1- causes a 32% content increase in 24-hydroxycholesterol (24SOH), the major oxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1- causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1- causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP and HMGR protein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.

Single nucleotide polymorphisms (SNPs) within the regulatory elements of a gene can alter gene expression, making these SNPs of prime importance for candidate gene association studies. We aimed to determine whether such regulatory variants are associated with clinical outcomes in three cohorts of patients with prostate cancer. We used RegulomeDB to identify potential regulatory variants based on in silico predictions and reviewed genome‐wide experimental findings. Overall, 131 putative regulatory SNPs with the highest confidence score on predicted functionality were investigated in two independent localized prostate cancer cohorts totalling 458 patients who underwent radical prostatectomy. The statistically significant SNPs identified in these two cohorts were then tested in an additional cohort of 504 patients with advanced prostate cancer. We identified one regulatory SNPs, rs1646724, that are consistently associated with increased risk of recurrence in localized disease (P = .003) and mortality in patients with advanced prostate cancer (P = .032) after adjusting for known clinicopathological factors. Further investigation revealed that rs1646724 may affect expression of SLC35B4, which encodes a glycosyltransferase, and that down‐regulation of SLC35B4 by transfecting short hairpin RNA in DU145 human prostate cancer cell suppressed proliferation, migration and invasion. Furthermore, we found increased SLC35B4 expression correlated with more aggressive forms of prostate cancer and poor patient prognosis. Our study provides robust evidence that regulatory genetic variants can affect clinical outcomes.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer involving epithelial squamous-cell carcinoma of the nasopharynx that mainly occurs in individuals from East and Southeast Asia. We investigated whether Chinese herbal medicine (CHM) as a complementary therapy offers benefits to these patients. We retrospectively evaluated the Taiwan Cancer Registry (Long Form) database for patients with advanced NPC, using or not using CHM, between 2007–2013. Cox proportional-hazard model and Kaplan‒Meier survival analyses were applied for patient survival. CHM-users showed a lower overall and cancer-related mortality risk than non-users. For advanced NPC patients, the overall mortality risk was 0.799-fold for CHM-users, after controlling for age, gender, and Charlson comorbidity index (CCI) score (Cancer stages 3 + 4: adjusted hazard ratio [aHR]: 0.799, 95% confidence interval [CI]: 0.676–0.943, p = 0.008). CHM-users also showed a lower cancer-related mortality risk than non-users (aHR: 0.71, 95% CI: 0.53–0.96, p = 0.0273). Association rule analysis showed that CHM pairs were Ban-Zhi-Lian (BZL; Scutellaria barbata D.Don ) and For single herbs, Bai-Hua-She-She-Cao (Herba Hedyotis Diffusae; Scleromitrion diffusum (Willd.) R.J.Wang (syn. Hedyotis diffusa Willd.) and Mai-Men-Dong (MMD; Ophiopogon japonicus (Thunb.) Ker Gawl. ), and Gan-Lu-Yin (GLY) and BHSSC. Network analysis revealed that BHSSC was the core CHM, and BZL, GLY, and Xin-Yi-Qing-Fei-Tang (XYQFT) were important CHMs in cluster 1. In cluster 2, ShengDH, MMD, Xuan-Shen (XS; Scrophularia ningpoensis Hensl. ), and Gua-Lou-Gen (GLG; Trichosanthes kirilowii Maxim. ) were important CHMs. Thus, as a complementary therapy, CHM, and particularly the 8 CHMs identified, are important for the treatment of advanced NPC patients.

Background: A few studies have investigated the interaction between exposure to road traffic noise, air pollutants, and cardiovascular disease (CVD), but their results were inconsistent. This cross-sectional study investigated whether road traffic noise, particulate matter with dynamic diameter less than 10 μm (PM10) and nitrogen dioxides (NO2) exposure were independently associated with the risk of CVD. Methods: We recruited 663 volunteers who had been living near main roads for more than three years in 2008. Information concerning the subjects’ home addresses was combined with noise measurements at 42 locations and annual average of air pollutants from 2 monitoring stations to estimate individual exposure. Multivariate logistic regression was used to calculate the odds ratio (OR) for diagnosed CVD, adjusting for potential confounders and co-exposure. Results: Only per 5-dBA increase in road traffic noise was significantly associated with elevated risk of CVD (adjusted OR = 2.23, 95% confidence interval (CI) = 1.26–3.93) in the single-exposure models. Such association was aggravated (adjusted OR = 2.96, 95% CI = 1.41–6.23) after adjustment for total traffic and PM10 or NO2 in the two-exposure models. Conclusions: Road traffic noise exposure may be associated with the increasing prevalence of CVD. No synergistic association was observed between co-exposure to noise and air pollutants and the risk of CVD.

Background To determine the association between circadian pathway genetic variants and the risk of prostate cancer progression. Methods We systematically evaluated 79 germline variants in nine circadian pathway genes in a cohort of 458 patients with localized prostate cancer as the discovery phase. We then replicated the significant findings in another cohort of 324 men with more advanced disease. The association of each variant with prostate cancer progression was evaluated by a log-rank test and Cox regression. Results A single nucleotide polymorphism of the neuronal PAS domain protein 2 ( NPAS2 ) gene (rs6542993 A>T) was found to be associated with a significantly higher risk of disease progression in both localized ( P  = 0.001) and advanced ( P  = 0.039) prostate cancer cases. In silico analysis revealed decreased expression levels of NPAS2 in carriers of the T allele of rs6542993 compared with those carrying the A allele. Consistently, downregulation of NPAS2 expression was associated with more aggressive prostate cancer and poor progression-free survival (log-rank P  = 0.002). Conclusions The NPAS2 rs6542993 polymorphism may be a promising biomarker, and may shed light on the pathways that govern prostate cancer progression.

This study aimed to measure personal exposure to sulfuric acid in the electroplating industry to establish a predictive model and test its validation. We collected indoor air parameters and related information from four electroplating plants. Silica gel sorbents were used to collect air samples using high-performance ion chromatography. We collected air samples from three plants (i.e., Plant B, Plant C, and Plant D) and applied multiple linear regressions to build a predictive model. Eight samples collected from the fourth plant (i.e., Plant A) were used to validate the model. A total of 41 samples were collected with a mean of 25.0 ± 9.8 μg/m3 (range 12.1–51.7 μg/m3) in this study, including Plant A (8 samples, 17.5 ± 2.8 μg/m3, 13.0–22.0 μg/m3), Plant B (11 samples, 36.5 ± 9.7 μg/m3, 23.1–51.7 μg/m3), Plant C (11 samples, 16.4 ± 1.7 μg/m3, 12.1–17.8 μg/m3), and Plant D (11 samples, 27.4 ± 1.7 μg/m3, 24.1–29.9 μg/m3). Plant B was significantly higher in sulfuric acid than the other plants. Workers from the electroplating process plants were exposed to sulfuric acid at 29.0 ± 11.5 μg/m3. The predictive model for personal exposure to sulfuric acid fit the data well (r2 = 0.853; adjusted r2 = 0.837) and had an accuracy of 5.52 μg/m3 (bias ± precision; 4.98 ± 2.38 μg/m3), validated by the personal sampling of the fourth plant. This study observed that sulfuric acid exposure was lower than the permissible exposure level of 1000 μg/m3 in Taiwan and the United States, and only two samples were lower than the European Union standard of 50 μg/m3. The developed model can be applied in epidemiological studies to predict personal exposure to sulfuric acid in plants using electroplating.