ABSTRACT
The reciprocal coordination between cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver is essential for maintaining cholesterol homeostasis, yet the mechanisms governing the opposing regulation of these processes remain poorly understood. Here, we identify a hormone, Cholesin, which is capable of inhibiting cholesterol synthesis in the liver, leading to a reduction in circulating cholesterol levels. Cholesin is encoded by a gene with a previously unknown function (C7orf50 in humans; 3110082I17Rik in mice). It is secreted from the intestine in response to cholesterol absorption and binds to GPR146, an orphan G-protein-coupled receptor, exerting antagonistic downstream effects by inhibiting PKA signaling and thereby suppressing SREBP2-controlled cholesterol synthesis in the liver. Therefore, our results demonstrate that the Cholesin-GPR146 axis mediates the inhibitory effect of intestinal cholesterol absorption on hepatic cholesterol synthesis. This discovered hormone, Cholesin, holds promise as an effective agent in combating hypercholesterolemia and atherosclerosis.
Subject(s)
Cholesterol , Hormones , RNA-Binding Proteins , Animals , Humans , Mice , Cholesterol/metabolism , Hormones/genetics , Hormones/metabolism , Hypercholesterolemia/metabolism , Liver/metabolism , Signal Transduction , RNA-Binding Proteins/metabolismABSTRACT
Low signal-to-noise ratio (SNR) infrared point target detection and tracking is crucial to study regarding infrared remote sensing. In the low-SNR images, the intensive noise will submerge targets. In this letter, a saliency-guided double-stage particle filter (SGDS-PF) formed by the searching particle filter (PF) and tracking PF is proposed to detect and track targets. Before the searching PF, to suppress noise and enhance targets, the single-frame and multi-frame target accumulation methods are introduced. Besides, the likelihood estimation filter and image block segmentation are proposed to extract the likelihood saliency and obtain proper proposal density. Guided by this proposal density, the searching PF detects potential targets efficiently. Then, with the result of the searching PF, the tracking PF is adopted to track and confirm the potential targets. Finally, the path of the real targets will be output. Compared with the existing methods, the SGDS-PF optimizes the proposal density for low-SNR images. Using a few accurate particles, the searching PF detects potential targets quickly and accurately. In addition, initialized by the searching PF, the tracking PF can keep tracking targets using very few particles even under intensive noise. Furthermore, the parameters have been selected appropriately through experiments. Extensive experimental results show that the SGDS-PF has an outstanding performance in tracking precision, tracking reliability, and time consumption. The SGDS-PF outperforms the other advanced methods.
Subject(s)
Noise , Probability , Reproducibility of Results , Signal-To-Noise RatioABSTRACT
The intestine is responsible for nutrient absorption and orchestrates metabolism in different organs during feeding, a process which is partly controlled by intestine-derived hormones. However, it is unclear whether the intestine plays an important role in metabolism during fasting. Here we have identified a novel hormone, famsin, which is secreted from the intestine and promotes metabolic adaptations to fasting. Mechanistically, famsin is shed from a single-pass transmembrane protein, Gm11437, during fasting and then binds OLFR796, an olfactory receptor, to activate intracellular calcium mobilization. This famsin-OLFR796 signaling axis promotes gluconeogenesis and ketogenesis for energy mobilization, and torpor for energy conservation during fasting. In addition, neutralization of famsin by an antibody improves blood glucose profiles in diabetic models, which identifies famsin as a potential therapeutic target for treating diabetes. Therefore, our results demonstrate that communication between the intestine and other organs by a famsin-OLFR796 signaling axis is critical for metabolic adaptations to fasting.
Subject(s)
Blood Glucose , Fasting , Fasting/physiology , Blood Glucose/metabolism , Gluconeogenesis/physiology , Hormones/metabolism , Ketone Bodies/metabolism , Liver/metabolismABSTRACT
A change in the metabolic flux of glucose from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regarded as one hallmark of cancer. However, the mechanisms underlying the metabolic switch between aerobic glycolysis and OXPHOS are unclear. Here we show that the M2 isoform of pyruvate kinase (PKM2), one of the rate-limiting enzymes in glycolysis, interacts with mitofusin 2 (MFN2), a key regulator of mitochondrial fusion, to promote mitochondrial fusion and OXPHOS, and attenuate glycolysis. mTOR increases the PKM2:MFN2 interaction by phosphorylating MFN2 and thereby modulates the effect of PKM2:MFN2 on glycolysis, mitochondrial fusion and OXPHOS. Thus, an mTOR-MFN2-PKM2 signaling axis couples glycolysis and OXPHOS to modulate cancer cell growth.
Subject(s)
Carcinogenesis/metabolism , Carrier Proteins/physiology , GTP Phosphohydrolases/physiology , Membrane Proteins/physiology , Mitochondrial Proteins/physiology , TOR Serine-Threonine Kinases/physiology , Thyroid Hormones/physiology , Animals , Cells, Cultured , Glycolysis , Humans , Mitochondrial Dynamics , Oxidative Phosphorylation , Thyroid Hormone-Binding ProteinsABSTRACT
Asprosin is a fasting-induced hormone that promotes glucose production in the liver and stimulates appetite in the hypothalamus by activating the cAMP signaling pathway via an unknown G protein-coupled receptor (GPCR). However, the bona fide receptor of Asprosin is unclear. Here, we have identified that the olfactory receptor OLFR734 acts as a receptor of Asprosin to modulate hepatic glucose production. Olfr734 knockout mice show a blunted response to Asprosin, including attenuated cAMP levels and hepatic glucose production, and improved insulin sensitivity. As Olfr734 deficiency dramatically attenuates both fasting and high-fat-diet-induced glucose production, our results demonstrate a critical role of OLFR734 as a receptor of Asprosin to maintain glucose homeostasis during fasting and in obesity.
Subject(s)
Glucose/metabolism , Receptors, Odorant/metabolism , 3T3-L1 Cells , Animals , Cells, Cultured , HEK293 Cells , Hep G2 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Receptors, Odorant/deficiencySubject(s)
Lipid Metabolism , Lysosomes , Homeostasis , Lysosomes/metabolism , Glycosphingolipids/metabolismABSTRACT
Lysosomes are centers for nutrient sensing and recycling that allow mammals to adapt to starvation. Regulation of lysosome dynamics by internal nutrient signaling is well described, but the mechanisms by which external cues modulate lysosomal function are unclear. Here, we describe an essential role of the fasting-induced hormone fibroblast growth factor 21 (FGF21) in lysosome homeostasis in mice. Fgf21 deficiency impairs hepatic lysosomal function by blocking transcription factor EB (TFEB), a master regulator of lysosome biogenesis and autophagy. FGF21 induces mobilization of calcium from the endoplasmic reticulum, which activates the transcriptional repressor downstream regulatory element antagonist modulator (DREAM), and thereby inhibits expression of Mid1 (encoding the E3 ligase Midline-1). Protein phosphatase PP2A, a substrate of MID1, accumulates and dephosphorylates TFEB, thereby upregulating genes involved in lysosome biogenesis, autophagy and lipid metabolism. Thus, an FGF21-TFEB signaling axis links lysosome homeostasis with extracellular hormonal signaling to orchestrate lipid metabolism during fasting.