A novel peptide encoded by circ-SLC9A6 promotes lipid dyshomeostasis through the regulation of H4K16ac-mediated CD36 transcription in NAFLD.

BACKGROUND: As the leading cause of end-stage liver disease, nonalcoholic fatty liver disease (NAFLD) is mainly induced by lipid dyshomeostasis. The translation of endogenous circular RNAs (circRNAs) is closely related to the progression of various diseases, but the involvement of circRNAs in NAFLD has not been determined. METHODS: Combined high-throughput circRNA profiles were used to identify circRNAs with translational potential. The underlying molecular mechanisms were investigated by RNA sequencing, pull-down/MS and site-specific mutagenesis. RESULTS: In this study, we focused on circ-SLC9A6, an abnormally highly expressed circRNA in human and mouse liver tissue during NAFLD development that exacerbates metabolic dyshomeostasis in hepatocytes by encoding a novel peptide called SLC9A6-126aa in vivo and in vitro. YTHDF2-mediated degradation of m6A-modified circ-SLC9A6 was found to be essential for the regulation of SLC9A6-126aa expression. We further found that the phosphorylation of SLC9A6-126aa by AKT was crucial for its cytoplasmic localization and the maintenance of physiological homeostasis, whereas high-fat stress induced substantial translocation of unphosphorylated SLC9A6-126aa to the nucleus, resulting in a vicious cycle of lipid metabolic dysfunction. Nuclear SLC9A6-126aa promotes transcriptional activation of the target gene CD36 and enhances its occupancy of the CD36 promoter locus by regulating MOF-mediated histone H4K16 acetylation. Hepatic CD36 depletion significantly ameliorated hyperactivated MAPK signalling and lipid disturbance in SLC9A6-126aa transgenic mice. Clinically, increasing levels of SLC9A6-126aa were observed during NAFLD progression and were found to be positively correlated with the CD36 and MAPK cascades. CONCLUSION: This study revealed the role of circ-SLC9A6-derived SLC9A6-126aa in the epigenetic modification-mediated regulation of lipid metabolism. Our findings may provide promising therapeutic targets for NAFLD and new insights into the pathological mechanisms of metabolic diseases. HIGHLIGHTS: Under normal circumstances, driven by m6A modification, YTHDF2 directly recognizes and degrades circ-SLC9A6, thereby inhibiting the translation of SLC9A6-126aa. Additionally, AKT1 phosphorylates and inhibits the nuclear translocation of SLC9A6-126aa. In NAFLD, lipid overload leads to YTHDF2 and AKT1 deficiency, ultimately increasing the expression and nuclear import of SLC9A6-126aa. Nuclear SLC9A6-126aa binds directly to the CD36 promoter and initiates CD36 transcription, which induces lipid dyshomeostasis.

Accurate Discrimination of Benign Biliary Diseases and Cholangiocarcinoma with Serum Multiomics Revealed by High-Throughput Nanoassisted Laser Desorption Ionization Mass Spectrometry.

Cholangiocarcinoma (CCA) is an aggressive malignant tumor with a poor prognosis. Carbohydrate antigen 19-9 is an essential biomarker for CCA diagnosis, but its low sensitivity (72%) makes the diagnosis unreliable. To explore potential biomarkers for the diagnosis of CCA, a high-throughput nanoassisted laser desorption ionization mass spectrometry technique was constructed. We performed serum lipidomics and peptidomics analyses from 112 patients with CCA and 123 patients with benign biliary diseases. Lipidomics analysis showed that various lipids, such as glycerophospholipids, glycerides, and sphingolipids, were perturbed. Peptidomics analysis revealed perturbations of multiple proteins involved in the coagulation cascade, lipid transport, and so on. After data mining, 25 characteristic molecules including 20 lipids and 5 peptides were identified as potential diagnostic biomarkers. After screening various machine learning algorithms, artificial neural network was selected to construct a multiomics model for CCA diagnosis with 96.5% sensitivity and 96.4% specificity. The sensitivity and specificity of the model in the independent test cohort were 93.8 and 87.5%, respectively. Furthermore, integrated analysis with transcriptomic data in the cancer genome atlas confirmed that genes altered in CCA significantly affected multiple lipid- and protein-related pathways. Data are available via MetaboLights with the identifier MTBLS6712.

Antihypertension Nanoblockers Increase Intratumoral Perfusion of Sequential Cytotoxic Nanoparticles to Enhance Chemotherapy Efficacy against Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), one of the worst prognosis types of tumors, is characterized by dense extracellular matrix, which compresses tumor vessels and forms a physical barrier to inhibit therapeutic drug penetration and efficacy. Herein, losartan, an antihypertension agent, is applied as a tumor stroma modulator and developed into a nanosystem. A series of lipophilic losartan prodrugs are constructed by esterification of the hydroxyl group on losartan to fatty acids. Based on the self-assembly ability and hydrodynamic diameter, the losartan-linoleic acid conjugate is selected for further investigation. To improve the stability in vivo, nanoassemblies are refined with PEGylation to form losartan nanoblocker (Los NB), and administered via intravenous injection for experiments. On murine models of pancreatic cancer, Los NB shows a greater ability to remodel the tumor microenvironment than free losartan, including stromal depletion, vessel perfusion increase, and hypoxia relief. Furthermore, Los NB pretreatment remarkably enhances the accumulation and penetration of 7-ethyl-10-hydroxycamptothecin (SN38)-loaded nanodrugs (SN38 NPs) in tumor tissues. Expectedly, overall therapeutic efficacy of SN38 NPs is significantly enhanced after Los NB pretreatment. Since losartan is one of the most commonly used antihypertension agents, this study may provide a potential for clinical transformation in stroma-rich PDAC treatment.

High nuclear ABCG1 expression is a poor predictor for hepatocellular carcinoma patient survival.

BACKGROUND: ATP-binding cassette transporter G1 (ABCG1) regulates cellular cholesterol homeostasis and plays a significant role in tumor immunity. But, for hepatocellular carcinoma (HCC), the role of ABCG1 has not been investigated. Thus, the aim of this study was to evaluate the prognostic value and clinicopathological significance of ABCG1 in HCC. METHODS: One hundred and four adult patients with HCC were enrolled, and ABCG1 expression in paired HCC specimens was determined by immunohistochemistry. All these patients were stratified by ABCG1 expression, Kaplan-Meier analysis was used to compare the overall survival (OS) and recurrence-free survival (RFS), and Cox regression analysis was used to determine independent predictors of tumor recurrence. RESULTS: Upregulation of ABCG1 was observed in HCC samples compared to matched tumor-adjacent tissues. Patients with high nuclear ABCG1 expression had lower OS and RFS (P = 0.012 and P = 0.020, respectively). High nuclear ABCG1 expression was related to larger tumor size (P = 0.004) and tumor recurrence (P = 0.027). Although ABCG1 was expressed in the cytoplasm, cytosolic expression could not predict the outcome in patients with HCC. A new stratification pattern was established based on the heterogenous ABCG1 expression pattern: high risk (Highnucleus/Lowcytosol), moderate risk (Highnucleus/Highcytosol or Lownucleus/Lowcytosol), and low risk (Lownucleus/Highcytosol). This ABCG1-based risk stratification could distinguish the different OS and RFS in patients with HCC. Multivariate Cox regression analysis indicated that ABCG1 high risk was an independent predictor of poor RFS (P = 0.015). CONCLUSIONS: High nuclear ABCG1 expression indicates poor prognosis in patients with HCC. Asymmetric distribution of ABCG1 in the nucleus and cytoplasm may have an important role in tumor recurrence.

Three-dimensional modeling in complex liver surgery and liver transplantation.

Liver resection and transplantation are the most effective therapies for many hepatobiliary tumors and diseases. However, these surgical procedures are challenging due to the anatomic complexity and many anatomical variations of the vascular and biliary structures. Three-dimensional (3D) printing models can clearly locate and describe blood vessels, bile ducts and tumors, calculate both liver and residual liver volumes, and finally predict the functional status of the liver after resection surgery. The 3D printing models may be particularly helpful in the preoperative evaluation and surgical planning of especially complex liver resection and transplantation, allowing to possibly increase resectability rates and reduce postoperative complications. With the continuous developments of imaging techniques, such models are expected to become widely applied in clinical practice.