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Therefore, exendin-4 decreased hepatic lipid content. ChIP showed that PREB could directly bind to the ABCA1 promoter, which was enhanced by exendin-4. Moreover, PREB stimulated ABCA1 promoter activity, and mutation of PREB-binding site in ABCA1 promoter cancelled exendin-4-enhanced ABCA1 promoter activity. Silencing of PREB attenuated the effect of exendin-4 and induced hepatic cholesterol accumulation. Blockade of CaMKK by STO-609 or siRNA cancelled the upregulation of ABCA1 and PREB induced by exendin-4. In vivo, exendin-4 or overexpression of PREB increased hepatic ABCA1 expression and decreased hepatic lipid accumulation and high plasma cholesterol caused by a HFD. CONCLUSIONS Our data shows that exendin-4 stimulates hepatic ABCA1 expression and decreases lipid accumulation by the CaMKK/CaMKIV/PREB pathway, suggesting that ABCA1 and PREB might be the therapeutic targets in fatty liver disease. OBJECTIVE Enteroendocrine cells (EECs) survey the gut luminal environment and coordinate hormonal, immune and neuronal responses to it. They exhibit well-characterised physiological roles ranging from the control of local gut function to whole body metabolism, but little is known regarding the regulatory networks controlling their differentiation, especially in the human gut. The small molecule isoxazole-9 (ISX-9) has been shown to stimulate neuronal and pancreatic beta-cell differentiation, both closely related to EEC differentiation. Our aim was to use ISX-9 as a tool to explore EEC differentiation. METHODS We investigated the effects of ISX-9 on EEC differentiation in mouse and human intestinal organoids, using real-time quantitative polymerase chain reaction (RT-qPCR), fluorescent-activated cell sorting, immunostaining and single-cell RNA sequencing. RESULTS ISX-9 increased the number of neurogenin3-RFP (Ngn3)-positive endocrine progenitor cells and upregulated NeuroD1 and Pax4, transcription factors thatven their diverse roles, understanding endocrine lineage plasticity and its control could have multiple therapeutic implications. OBJECTIVE In mouse models, deficiency of TTC39B (T39) decreases hepatic lipogenic gene expression and protects against diet-induced steatohepatitis. While assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting T39, we discovered an unexpected weight loss phenotype. The objective of this study was to determine the mechanism of the resistance to diet-induced obesity. METHODS To assess therapeutic potential, we used antisense oligonucleotides (ASO) to knock down T39 expression in a Western or high-fat, high-cholesterol, high-sucrose-diet-fed Ldlr-/- or wild-type mice. RESULTS T39 ASO treatment led to decreased hepatic lipogenic gene expression and decreased hepatic triglycerides. Unexpectedly, T39 ASO treatment protected against diet-induced obesity. The reduced weight gain was seen with two different ASOs that decreased T39 mRNA in adipose tissue macrophages (ATMs), but not with a liver-targeted GalNac-ASO. Mice treated with the T39 ASO displayed increased browning of gonadal white adipose tissue (gWAT) and evidence of increased lipolysis. However, T39 knockout mice displayed a similar weight loss response when treated with T39 ASO, indicating an off-target effect. RNA-seq analysis of gWAT showed a widespread increase in type I interferon (IFN)-responsive genes, and knockout of the IFN receptor abolished the weight loss phenotype induced by the T39 ASO. Some human T39 ASOs and ASOs with different modifications targeting LDLR also induced a type I IFN response in THP1 macrophages. CONCLUSION Our data suggest that extrahepatic targeting of T39 by ASOs in ATMs produced an off-target type 1 IFN response, leading to activation of lipolysis, browning of WAT, and weight loss. While our findings suggest that ASOs may induce off-target type 1 IFN response more commonly than previously thought, they also suggest that therapeutic induction of type 1 IFN selectively in ATMs could potentially represent a novel approach to the treatment of obesity. OBJECTIVE The most common kidney cancer, clear cell renal cell carcinoma (ccRCC), is closely associated with obesity. The "clear cell" variant of RCC gets its name from the large lipid droplets that accumulate in the tumor cells. Although renal lipid metabolism is altered in ccRCC, the mechanisms and lipids driving this are not well understood. METHODS We used shotgun lipidomics in human ccRCC tumors and matched normal adjacent renal tissue. To assess MBOAT7s gene expression across tumor severity, we examined histologically graded human ccRCC samples. We then utilized genome editing in ccRCC cell lines to understand the role of MBOAT7 in ccRCC progression. RESULTS We identified a lipid signature for ccRCC that includes an increase in arachidonic acid-enriched phosphatidylinositols (AA-PI). In parallel, we found that ccRCC tumors have increased expression of acyltransferase enzyme membrane bound O-acyltransferase domain containing 7 (MBOAT7) that contributes to AA-PI synthesis. In ccRCC patients, MBOAT7 expression increases with tumor grade, and increased MBOAT7 expression correlates with poor survival. Genetic deletion of MBOAT7 in ccRCC cells decreases proliferation and induces cell cycle arrest, and MBOAT7-/- cells fail to form tumors in vivo. RNAseq of MBOAT7-/- cells identified alterations in cell migration and extracellular matrix organization that were functionally validated in migration assays. CONCLUSIONS This study highlights the accumulation of AA-PI in ccRCC and demonstrates a novel way to decrease the AA-PI pool in ccRCC by limiting MBOAT7. Our data reveal that metastatic ccRCC is associated with altered AA-PI metabolism and identify MBOAT7 as a novel target in advanced ccRCC. OBJECTIVE Considerable uncertainty remains regarding the veracity of measuring myokine irisin more than seven years after its original description. Unresolved issues include the nature of transcription of the irisin precursor fibronectin type III domain containing 5 (FNDC5) gene across species, the reliability of irisin levels measured with commercial enzyme-linked immunosorbent assays (ELISAs), and the overall validity of the recently published reference values for human serum measured with quantitative mass spectrometry. We utilized multiple species and measures to evaluate the robustness of commonly used reagents and methods for reporting irisin. METHODS Amplification of cDNA was used to assess the FNDC5 transcript patterns in humans and mice. https://www.selleckchem.com/products/tasin-30.html The specificity and sensitivity of different irisin antibodies were examined via western blotting. Quantification of circulating native irisin was conducted with mass spectrometry using an absolute quantification peptide for irisin. RESULTS We show that there is a greater transcript diversity of human FNDC5 than currently annotated, but no indication of the expression of transcripts leading to a truncated form of irisin.