Background & Aims It is important to increase our understanding of gustatory detection of dietary fat and its contribution to fat preference. We studied the roles of the fat taste receptors CD36 and GPR120 and their interactions via Ca2+ signaling in fungiform taste bud cells (TBC). Methods We measured Ca2+ signaling in human TBC, transfected with small interfering RNAs (siRNAs) against mRNAs encoding CD36 and GPR120 (or control siRNAs). We also studied Ca2+ signaling in TBC from CD36−/− mice and from wild-type lean and obese mice. Additional studies were conducted with mouse enteroendocrine cell line STC-1 that express GPR120 and stably transfected with human CD36. We measured release of serotonin and GLP-1 from human and mice TBC in response to CD36 and GPR120 activation. Results High concentrations of linoleic acid induced Ca2+ signaling via CD36 and GPR120 in human and mice TBC as well as in STC-1 cells, whereas low concentrations induced Ca2+ signaling via only CD36. Incubation of human and mice fungiform TBC with lineoleic acid downregulated CD36 and upregulated GPR120 in membrane lipid rafts. Obese mice had decreased spontaneous preference for fat. Fungiform TBC from obese mice had reduced Ca2+ and serotonin responses but increased release of GLP1, along with reduced levels of CD36 and increased levels of GPR120 in lipid rafts. Conclusions CD36 and GPR120 have non-overlapping roles in TBC signaling during oro-gustatory perception of dietary lipids; these are differentially regulated by obesity.
Heat shock protein 27 (HSP27) is a chaperone whose cellular expression increases in response to various stresses and protects the cell either by inhibiting apoptotic cell death or by promoting the ubiquitination and proteasomal degradation of specific proteins. Here, we show that globin transcription factor 1 (GATA-1) is a client protein of HSP27. In 2 models of erythroid differentiation; that is, in the human erythroleukemia cell line, K562 induced to differentiate into erythroid cells on hemin exposure and CD34 ؉ human cells ex vivo driven to erythroid differentiation in liquid culture, depletion of HSP27 provokes an accumulation of GATA-1 and impairs terminal maturation. More specifically, we demonstrate that, in the late stages of the erythroid differentiation program, HSP27 is phosphorylated in a p38-dependent manner, enters the nucleus, binds to GATA-1, and induces its ubiquitination and proteasomal degradation, provided that the transcription factor is acetylated. We conclude that HSP27 plays a role in the fine-tuning of terminal erythroid differentiation through regulation of GATA-1 content and activity. (Blood. 2010;116(1):85-96) IntroductionTerminal erythroid differentiation is driven by the glycoprotein hormone erythropoietin (Epo) and involves the sequential formation of proerythroblasts and basophilic, polychromatic, and orthochromatic erythroblasts in the bone marrow. This differentiation program is under control of the transcription factor GATA-1 (globin transcription factor 1), 1,2 which induces the expression of erythroid genes such as glycophorin A, Epo receptor, and hemoglobin. 3 GATA-1 also cooperates with Epo to promote erythroid precursor survival by positively regulating the bcl-x L gene. 3-5 On Epo starvation or engagement of the death receptor Fas (CD95/APO-1), caspases are activated and GATA-1 is cleaved. These events arrest erythroid precursor maturation and provoke cell death. 6,7 On Epo stimulation of erythroid precursors, caspase-3 is also transiently activated, and this activation is required for terminal erythroblast maturation, but GATA-1 remains uncleaved and erythroid cells do not die. [8][9][10] We have demonstrated that, in Epo-stimulated erythroid precursors, GATA-1 was protected from caspase-3-mediated cleavage by the stress-inducible heat shock protein 70 (HSP70). At the onset of caspase-3 activation, HSP70 translocates from the cytoplasm to the nucleus and interacts with GATA-1. Epo deprivation disrupts the GATA-1/HSP70 interaction and exposes GATA-1 to the proteolytic effect of caspase-3. 11 Another stress-inducible HSP that is expressed in erythroid cells undergoing differentiation is HSP27. 11 This small stress protein has shown prosurvival functions through interaction with proteins such as cytochrome c, caspase-3, death domainassociated protein, and actin (for a review, see Lanneau et al 12 ).HSP27 is also an adenosine triphosphate (ATP)-independent chaperone that binds ubiquitin, with a higher affinity for long chains of ubiquitin than for mono-ubiquitin, and orches...
Obesity is a major public health problem. An in-depth knowledge of the molecular mechanisms of oro-sensory detection of dietary lipids may help fight it. Humans and rodents can detect fatty acids via lipido-receptors, such as CD36 and GPR120. We studied the implication of the MAPK pathways, in particular, ERK1/2, in the gustatory detection of fatty acids. Linoleic acid, a dietary fatty acid, induced via CD36 the phosphorylation of MEK1/2-ERK1/2-ETS-like transcription factor-1 cascade, which requires Fyn-Src kinase and lipid rafts in human taste bud cells (TBCs). ERK1/2 cascade was activated by Ca signaling via opening of the calcium-homeostasis modulator-1 (CALHM1) channel. Furthermore, fatty acid-evoked Ca signaling and ERK1/2 phosphorylation were decreased in both human TBCs after small interfering RNA knockdown of CALHM1 channel and in TBCs from Calhm1 mice. Targeted knockdown of ERK1/2 by small interfering RNA or PD0325901 (MEK1/2 inhibitor) in the tongue and genetic ablation of Erk1 or Calhm1 genes impaired preference for dietary fat in mice. Lingual inhibition of ERK1/2 in healthy volunteers also decreased orogustatory sensitivity for linoleic acid. Our data demonstrate that ERK1/2-MAPK cascade is regulated by the opening of CALHM1 Ca channel in TBCs to modulate orogustatory detection of dietary lipids in mice and humans.-Subramaniam, S., Ozdener, M. H., Abdoul-Azize, S., Saito, K., Malik, B., Maquart, G., Hashimoto, T., Marambaud, P., Aribi, M., Tordoff, M. G., Besnard, P., Khan, N. A. ERK1/2 activation in human taste bud cells regulates fatty acid signaling and gustatory perception of fat in mice and humans.
Objectives: Zizyphus lotus L. is a medicinal plant, used in traditional medicine for its multiple therapeutic properties. The aim of the present study was to determine the antidiabetic and antioxidant effects of aqueous extracts of different parts of Zizyphus lotus in diabetic Wistar rats. Research methods and procedures: The male Wistar rats were rendered diabetic by intraperitoneal (i.p.) injection of streptozotocin (40 mg/kg body weight). Aqueous extracts from different parts, i.e, root, leaf, and seed of Zizyphus lotus L. were prepared and administrated orally to the animals at the dose of 300 mg/kg for 21 days. Blood glucose level was measured, and antioxidant status was assessed by determining oxygen radical absorbance capacity (ORAC) and the activities of enzymes like catalase, glutathione reductase and peroxidase in pancreas, liver, and erythrocytes. Vitamin C levels were determined by precipitating with 10% trichloroacetic acid. Vitamins A and E concentrations were measured by HPLC. Results: The leaf and root, but not seed, extracts exerted the glucose lowering effect on 21 st day of postadministration. The leaf and root extracts corrected antioxidant status of diabetic animals in pancreas, liver and erythrocytes. The concentrations of different vitamins (vitamin A, C and E) in diabetic rats were also modulated by leaf and root, but not seed, extracts. Conclusion(s): Our study shows that oral administration of Zizyphus lotus L. extracts from roots and leaves exerted antidiabetic and antioxidant effects in diabetic rats. Z. lotus L. seems to be a good candidate to lower, in addition to conventional antidiabetic drugs, the hyperglycaemia in diabetic subjects.
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