Sensing mechanisms for nutrients, in particular dietary fat, operate in the mouth, brain, and gastrointestinal tract and play a key role in regulating feeding behavior and energy balance. Critical to ...these regulatory mechanisms are the specialized receptors present on taste buds on the tongue, on neurons in specialized centers in the brain, and on epithelial and enteroendocrine cells in the intestinal mucosa. These receptors recognize nutrients and respond by inducing intracellular signals that trigger release of bioactive compounds that influence other organs and help coordinate the response to the meal. Components of dietary fat that are recognized by these receptors are the long-chain fatty acids that act as ligands for 2 G protein-coupled receptors, GPR40 and GPR120, and the fatty acid (FA) translocase/CD36. Recent evidence that emphasizes the important role of CD36 in orosensory, intestinal, and neuronal sensing of FAs under physiologic conditions is highlighted in the review. How this role intersects with that of GPR120 and GPR40 in the regulation of food preference and energy balance is briefly discussed.
Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich tubulovesicles (TVs) toward apical membranes in response to histamine stimulation via cyclic AMP ...elevation. Here, we found that TRPML1 (ML1), a protein that is mutated in type IV mucolipidosis (ML-IV), is a tubulovesicular channel essential for TV exocytosis and acid secretion. Whereas ML-IV patients are reportedly achlorhydric, transgenic overexpression of ML1 in mouse parietal cells induced constitutive acid secretion. Gastric acid secretion was blocked and stimulated by ML1 inhibitors and agonists, respectively. Organelle-targeted Ca2+ imaging and direct patch-clamping of apical vacuolar membranes revealed that ML1 mediates a PKA-activated conductance on TV membranes that is required for histamine-induced Ca2+ release from TV stores. Hence, we demonstrated that ML1, acting as a Ca2+ channel in TVs, links transmitter-initiated cyclic nucleotide signaling with Ca2+-dependent TV exocytosis in parietal cells, providing a regulatory mechanism that could be targeted to manage acid-related gastric diseases.
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•ML1 antagonists inhibit gastric acid secretion in parietal cells•Transgenic expression of ML1 in parietal cells causes constitutive acid secretion•ML1 is a Ca2+ release channel in the tubulovesicle•Histamine-PKA signaling activates ML1-dependent exocytosis of tubulovesicles
Acid secretion from the parietal cells of the stomach is essential for food digestion. Sahoo et al. identified TRPML1 as a histamine-activated Ca2+ channel in the tubulovesicles required for gastric acid secretion. Synthetic agonists and inhibitors of TRPML1 may be developed to control acid secretion and treat acid-related gastric diseases.
The metabolic syndrome (MetS) greatly increases risk of cardiovascular disease and diabetes and is generally associated with abnormally elevated postprandial triglyceride levels. We evaluated ...intestinal synthesis of triglyceride-rich lipoproteins (TRL) in a mouse model of the MetS obtained by feeding a palm oil-rich high fat diet (HFD). By contrast to control mice, MetS mice secreted two populations of TRL. If the smaller size population represented 44% of total particles in the beginning of intestinal lipid absorption in MetS mice, it accounted for only 17% after 4 h due to the secretion of larger size TRL. The MetS mice displayed accentuated postprandial hypertriglyceridemia up to 3 h due to a defective TRL clearance. These alterations reflected a delay in lipid induction of genes for key proteins of TRL formation (MTP, L-FABP) and blood clearance (ApoC2). These abnormalities associated with blunted lipid sensing by CD36, which is normally required to optimize jejunal formation of large TRL. In MetS mice CD36 was not downregulated by lipid in contrast to control mice. Treatment of controls with the proteosomal inhibitor MG132, which prevented CD36 downregulation, resulted in blunted lipid-induction of MTP, L-FABP and ApoC2 gene expression, as in MetS mice. Absence of CD36 sensing was due to the hyperinsulinemia in MetS mice. Acute insulin treatment of controls before lipid administration abolished CD36 downregulation, lipid-induction of TRL genes and reduced postprandial triglycerides (TG), while streptozotocin-treatment of MetS mice restored lipid-induced CD36 degradation and TG secretion. In vitro, insulin treatment abolished CD36-mediated up-regulation of MTP in Caco-2 cells. In conclusion, HFD treatment impairs TRL formation in early stage of lipid absorption via insulin-mediated inhibition of CD36 lipid sensing. This impairment results in production of smaller TRL that are cleared slowly from the circulation, which might contribute to the reported association of CD36 variants with MetS risk.
Purpose of review
Neuroendocrine tumors (NETs) were initially identified as a separate entity in the early 1900s as a unique malignancy that secretes bioactive amines. GI-NETs are the most frequent ...type and represent a unique subset of NETs, because at least 75% of these tumors represent gastrin stimulation of the enterochromaffin-like cell located in the body of the stomach.
The purpose of this review is to understand the specific role of gastrin in the generation of Gastric NETs (G-NETs).
Recent findings
We review here the origin of enterochromaffin cells gut and the role of hypergastrinemia in gastric enteroendocrine tumorigenesis. We describe generation of the first genetically engineered mouse model of gastrin-driven G-NETs that mimics the human phenotype. The common mechanism observed in both the hypergastrinemic mouse model and human carcinoids is translocation of the cyclin-dependent inhibitor p27
kip
to the cytoplasm and its subsequent degradation by the proteasome.
Summary
Therapies that block degradation of p27
kip
, the CCKBR2 gastrin receptor, or gastrin peptide are likely to facilitate treatment.
Background & Aims CD36 has immunometabolic actions and is abundant in the small intestine on epithelial, endothelial, and immune cells. We examined the role of CD36 in gut homeostasis by using mice ...null for CD36 (CD36KO) and with CD36 deletion specific to enterocytes (Ent-CD36KO) or endothelial cells (EC-CD36KO). Methods Intestinal morphology was evaluated by using immunohistochemistry and electron microscopy. Intestinal inflammation was determined from neutrophil infiltration and expression of cytokines, toll-like receptors, and cyclooxygenase-2. Barrier integrity was assessed from circulating lipopolysaccharide and dextran administered intragastrically. Epithelial permeability to luminal dextran was visualized by using two-photon microscopy. Results The small intestines of CD36KO mice fed a chow diet showed several abnormalities including extracellular matrix accumulation with increased expression of extracellular matrix proteins, evidence of neutrophil infiltration, inflammation, and compromised barrier function. Electron microscopy showed shortened desmosomes with decreased desmocollin 2 expression. Systemically, leukocytosis and neutrophilia were present together with 80% reduction of anti-inflammatory Ly6Clow monocytes. Bone marrow transplants supported the primary contribution of non-hematopoietic cells to the inflammatory phenotype. Specific deletion of endothelial but not of enterocyte CD36 reproduced many of the gut phenotypes of germline CD36KO mice including fibronectin deposition, increased interleukin 6, neutrophil infiltration, desmosome shortening, and impaired epithelial barrier function. Conclusions CD36 loss results in chronic neutrophil infiltration of the gut, impairs barrier integrity, and systemically causes subclinical inflammation. Endothelial cell CD36 deletion reproduces the major intestinal phenotypes. The findings suggest an important role of the endothelium in etiology of gut inflammation and loss of epithelial barrier integrity.
Ovarian cancer (OvCa) is characterized by widespread and rapid metastasis in the peritoneal cavity. Visceral adipocytes promote this process by providing fatty acids (FAs) for tumour growth. However, ...the exact mechanism of FA transfer from adipocytes to cancer cells remains unknown. This study shows that OvCa cells co-cultured with primary human omental adipocytes express high levels of the FA receptor, CD36, in the plasma membrane, thereby facilitating exogenous FA uptake. Depriving OvCa cells of adipocyte-derived FAs using CD36 inhibitors and short hairpin RNA knockdown prevented development of the adipocyte-induced malignant phenotype. Specifically, inhibition of CD36 attenuated adipocyte-induced cholesterol and lipid droplet accumulation and reduced intracellular reactive oxygen species (ROS) content. Metabolic analysis suggested that CD36 plays an essential role in the bioenergetic adaptation of OvCa cells in the adipocyte-rich microenvironment and governs their metabolic plasticity. Furthermore, the absence of CD36 affected cellular processes that play a causal role in peritoneal dissemination, including adhesion, invasion, migration and anchorage independent growth. Intraperitoneal injection of CD36-deficient cells or treatment with an anti-CD36 monoclonal antibody reduced tumour burden in mouse xenografts. Moreover, a matched cohort of primary and metastatic human ovarian tumours showed upregulation of CD36 in the metastatic tissues, a finding confirmed in three public gene expression data sets. These results suggest that omental adipocytes reprogram tumour metabolism through the upregulation of CD36 in OvCa cells. Targeting the stromal-tumour metabolic interface via CD36 inhibition may prove to be an effective treatment strategy against OvCa metastasis.
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