scholarly journals Novel identification of the free fatty acid receptor FFAR1 that promotes contraction in airway smooth muscle

2015 ◽  
Vol 309 (9) ◽  
pp. L970-L982 ◽  
Author(s):  
Kentaro Mizuta ◽  
Yi Zhang ◽  
Fumiko Mizuta ◽  
Hiroshi Hoshijima ◽  
Toshiya Shiga ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Smooth Muscle ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Guinea Pig ◽  
Free Fatty Acids ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Fiber Formation ◽  
Long Chain

Obesity is one of the major risk factors for asthma. Previous studies have demonstrated that free fatty acid levels are elevated in the plasma of obese individuals. Medium- and long-chain free fatty acids act as endogenous ligands for the free fatty acid receptors FFAR1/GPR40 and FFAR4/GPR120, which couple to Gq proteins. We investigated whether FFAR1 and FFAR4 are expressed on airway smooth muscle and whether they activate Gq-coupled signaling and modulate airway smooth muscle tone. We detected the protein expression of FFAR1 and FFAR4 in freshly dissected native human and guinea pig airway smooth muscle and cultured human airway smooth muscle (HASM) cells by immunoblotting and immunohistochemistry. The long-chain free fatty acids (oleic acid and linoleic acid) and GW9508 (FFAR1/FFAR4 dual agonist) dose-dependently stimulated transient intracellular Ca2+ concentration ([Ca2+]i) increases and inositol phosphate synthesis in HASM cells. Downregulation of FFAR1 or FFAR4 in HASM cells by small interfering RNA led to a significant inhibition of the long-chain free fatty acids-induced transient [Ca2+]i increases. Oleic acid, linoleic acid, or GW9508 stimulated stress fiber formation in HASM cells, potentiated acetylcholine-contracted guinea pig tracheal rings, and attenuated the relaxant effect of isoproterenol after an acetylcholine-induced contraction. In contrast, TUG-891 (FFAR4 agonist) did not induce the stress fiber formation or potentiate acetylcholine-induced contraction. These results suggest that FFAR1 is the functionally dominant free fatty acid receptor in both human and guinea pig airway smooth muscle. The free fatty acid sensors expressed on airway smooth muscle could be an important modulator of airway smooth muscle tone.

scholarly journals The short-chain free fatty acid receptor FFAR3 is expressed and potentiates contraction in human airway smooth muscle

2020 ◽  
Vol 318 (6) ◽  
pp. L1248-L1260 ◽  
Author(s):  
Kentaro Mizuta ◽  
Haruka Sasaki ◽  
Yi Zhang ◽  
Atsuko Matoba ◽  
Charles W. Emala
Keyword(s):  
Smooth Muscle ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Airway Smooth Muscle ◽  
Fiber Formation ◽  
Short Chain ◽  
Human Airway Smooth Muscle ◽  
Camp Synthesis ◽  
Human Airway ◽  
Chronic Activation

Emerging evidence suggests that gut microbiota-derived short-chain fatty acids (SCFAs; acetate, propionate, and butyrate) are important modulators of the inflammatory state in diseases such as asthma. However, the functional expression of the Gi protein-coupled free fatty acid receptors (FFAR2/GPR43 and FFAR3/GPR41) has not been identified on airway smooth muscle (ASM). Classically, acute activation of Gi-coupled receptors inhibits cyclic AMP (cAMP) synthesis, which impairs ASM relaxation and can also induce crosstalk between Gi- and Gq-signaling pathways, potentiating increases in intracellular Ca2+ concentration ([Ca2+]i), favoring ASM contraction. In contrast, chronic activation of Gi-coupled receptors can sensitize adenylyl cyclase resulting in increased cAMP synthesis favoring relaxation. We questioned whether the Gi-coupled FFAR2 or FFAR3 is expressed in human ASM, whether they modulate cAMP and [Ca2+]i, and whether SCFAs modulate human ASM tone. We detected the protein expression of FFAR3 but not FFAR2 in native human ASM and primary cultured human airway smooth muscle (HASM) cells. In HASM cells, acute activation of FFAR3 with SCFAs inhibited forskolin-stimulated cAMP accumulation, but chronic activation did not sensitize cAMP synthesis. SCFAs induced [Ca2+]i increases that were attenuated by pertussis toxin, gallein, U73122, or xestospongin C. Acute treatment with SCFAs potentiated acetylcholine-stimulated [Ca2+]i increases and stress fiber formation in cells and contraction of ex vivo human airway tissues. In contrast, chronic pretreatment of human ASM with propionate did not potentiate airway relaxation. Together, these findings demonstrate that FFAR3 is expressed in human ASM and contributes to ASM contraction via reduced cAMP and increased [Ca2+]i.

THE EFFECT OF FREE FATTY ACIDS ON RESIN UPTAKE OF TRI-IODOTHYRONINE FROM HUMAN, RAT, RABBIT AND GUINEA-PIG SERUM AND HUMAN SERUM ALBUMIN

1969 ◽  
Vol 45 (4) ◽  
pp. 489-493 ◽  
Author(s):  
P. W. NATHANIELSZ
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Human Serum Albumin ◽  
Guinea Pig ◽  
Serum Albumin ◽  
Free Fatty Acids ◽  
Human Serum ◽  
Rat Serum ◽  
Pig Serum

SUMMARY Recently changes in plasma free fatty acids have been suggested as a possible regulator of the levels of free thyroxine in the plasma. Oleic acid has been shown to displace tri-iodothyronine from human serum, human serum albumin, rat serum, rabbit serum and guinea-pig serum. The extent of the displacement, much greater from human serum albumin than from whole serum, suggests that free fatty acid does not affect the globulin binding site. It would also appear that, in the rat, all the binding sites are sensitive to free fatty acids and hence there is probably only albumin binding in this species. The results with rabbit and guinea-pig serum were intermediate to those with human and rat serum. A significant rise in resin uptake of tri-iodothyronine in vitro occurred with an increase of free fatty acid level of 0·5 m-equiv./l., well within the physiological range.

Melatonin MT2 receptor is expressed and potentiates contraction in human airway smooth muscle

2021 ◽  
Author(s):  
Haruka Sasaki ◽  
Yi Zhang ◽  
Charles W Emala ◽  
Kentaro Mizuta
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Fiber Formation ◽  
Melatonin Receptors ◽  
Human Airway Smooth Muscle ◽  
Nocturnal Asthma ◽  
Smooth Muscle Tone ◽  
Human Airway

Nocturnal asthma is characterized by heightened bronchial reactivity at night, and plasma melatonin concentrations are higher in patients with nocturnal asthma symptoms. Numerous physiological effects of melatonin are mediated via its specific G protein-coupled receptors (GPCRs) named the MT1 receptor which couples to both Gq and Gi proteins, and the MT2 receptor which couples to Gi. We investigated whether melatonin receptors are expressed on airway smooth muscle, whether they regulate intracellular cyclic AMP (cAMP) and calcium concentrations ([Ca2+]i) which modulate airway smooth muscle tone, and whether they promote airway smooth muscle cell proliferation. We detected the mRNA and protein expression of the melatonin MT2 but not the MT1 receptor in native human and guinea pig airway smooth muscle and cultured human airway smooth muscle (HASM) cells by RT-PCR, immunoblotting, and immunohistochemistry. Activation of melatonin MT2 receptors with either pharmacological concentrations of melatonin (10 - 100 µM) or the non-selective MT1/MT2 agonist ramelteon (10 µM) significantly inhibited forskolin-stimulated cAMP accumulation in HASM cells, which was reversed by the Gαi protein inhibitor pertussis toxin or knockdown of the MT2 receptor by its specific siRNA. Although melatonin by itself did not induce an initial [Ca2+]i increase and airway contraction, melatonin significantly potentiated acetylcholine-stimulated [Ca2+]i increases, stress fiber formation through the MT2 receptor in HASM cells, and attenuated the relaxant effect of isoproterenol in guinea pig trachea. These findings suggest that the melatonin MT2 receptor is expressed in ASM, and modulates airway smooth muscle tone via reduced cAMP production and increased [Ca2+]i.

Effect of insulin on free fatty acid uptake by hepatocytes in the duck

1984 ◽  
Vol 102 (3) ◽  
pp. 381-386 ◽  
Author(s):  
R. Gross ◽  
P. Mialhe
Keyword(s):  
Fatty Acids ◽  
Growth Hormone ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Glucose Metabolism ◽  
Free Fatty Acids ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
Low Doses ◽  
Higher Doses

ABSTRACT To elucidate the hypolipacidaemic effect of insulin in ducks, its action on the uptake of free fatty acids (FFA) by duck hepatocytes was determined. At low doses (10 mu./l) insulin stimulated FFA uptake. This effect was not observed with higher doses of insulin (20, 30 and 50 mu./l). Growth hormone at physiological concentrations and corticosterone (14·4 nmol/l) decreased basal activity, probably by reducing glucose metabolism and consequently α-glycerophosphate (α-GP) supply. Insulin was able to reverse the inhibition induced by GH and corticosterone on both FFA uptake and α-GP production. These results therefore suggest that the hypolipacidaemic effect of insulin may be partly mediated by its action on hepatic FFA uptake. J. Endocr. (1984) 102, 381–386

scholarly journals Free Fatty acids receptors (FFAR2 and FFAR3) control cell proliferation by regulating cellular glucose uptake

2019 ◽  
Author(s):  
Mohammad Aziz ◽  
Saeed Al Mahri ◽  
Amal Alghamdi ◽  
Maaged AlAkiel ◽  
Monira Al Aujan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fatty Acids ◽  
Cell Proliferation ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Free Fatty Acids ◽  
Glucose Uptake ◽  
Microarray Data ◽  
Free Fatty Acid Receptors

Abstract Background Colorectal cancer is a worldwide problem which has been associated with changes in diet and lifestyle pattern. As a result of colonic fermentation of dietary fibres, short chain free fatty acids are generated which activate Free Fatty Acid Receptors 2 and 3 (FFAR2 and FFAR3). FFAR2 and FFAR3 genes are abundantly expressed in colonic epithelium and play an important role in the metabolic homeostasis of colonic epithelial cells. Earlier studies point to the involvement of FFAR2 in colorectal carcinogenesis. Methods Transcriptome analysis console was used to analyse microarray data from patients and cell lines. We employed shRNA mediated down regulation of FFAR2 and FFAR3 genes which was assessed using qRT-PCR. Assays for glucose uptake and cAMP generation was done along with immunofluorescence studies. For measuring cell proliferation, we employed real time electrical impedance based assay available from xCelligence. Results Microarray data analysis of colorectal cancer patient samples showed a significant down regulation of FFAR2 gene expression. This prompted us to study the FFAR2 in colorectal cancer. Since, FFAR3 shares significant structural and functional homology with FFAR2, we knocked down both these receptors in colorectal cancer cell line HCT 116. These modified cell lines exhibited higher proliferation rate and were found to have increased glucose uptake as well as increased level of GLUT1. Since, FFAR2 and FFAR3 signal through G protein subunit (Gαi), knockdown of these receptors was associated with increased cAMP. Inhibition of PKA did not alter the growth and proliferation of these cells indicating a mechanism independent of cAMP/PKA pathway. Conclusion: Our results suggest role of FFAR2/FFAR3 genes in increased proliferation of colon cancer cells via enhanced glucose uptake and exclude the role of protein kinase A mediated cAMP signalling. Alternate pathways could be involved that would ultimately result in increased cell proliferation as a result of down regulated FFAR2/FFAR3 genes. This study paves the way to understand the mechanism of action of short chain free fatty acid receptors in colorectal cancer.

Epinephrine-insulin antagonism on free fatty acid release

1961 ◽  
Vol 201 (5) ◽  
pp. 815-818 ◽  
Author(s):  
John J. Spitzer ◽  
William T. McElroy
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Free Fatty Acids ◽  
Blood Sugar ◽  
Drug Administration ◽  
Hepatic Uptake ◽  
Fatty Acid Release ◽  
Plasma Ffa ◽  
Acid Release

The effects of epinephrine or norepinephrine were studied in dogs receiving insulin plus glucose prior to and during administration of the amine. Epinephrine caused a significantly smaller elevation of free fatty acids (FFA) with than without insulin plus glucose administration. Blood sugar responses were quantitatively similar. Epinephrine increased both hepatic uptake of FFA and hepatic release of glucose; these changes were similar to the ones found previously in dogs not receiving insulin plus glucose. The action of norepinephrine on elevating plasma FFA was only slightly and not significantly affected by the administration of insulin plus glucose. When the order of drug administration was reversed, infusion of insulin plus glucose lowered plasma FFA levels and hepatic FFA uptake in animals already receiving either epinephrine or nonepinephrine.

Changes in plasma free fatty acid concentrations on passage through the dog kidney

1961 ◽  
Vol 200 (5) ◽  
pp. 1095-1098 ◽  
Author(s):  
Frank J. Hohenleitner ◽  
John J. Spitzer
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Free Fatty Acids ◽  
Renal Plasma Flow ◽  
Plasma Free Fatty Acid ◽  
Systemic Artery ◽  
Arterial Concentration ◽  
Dog Kidney ◽  
Anesthetized Dogs

To measure the renal removal of free fatty acids from the plasma, simultaneous determinations of this metabolite were performed in a systemic artery and a renal vein in the anesthetized dogs. Renal plasma flow was also determined by the PAH method, and the renal uptake of free fatty acids was calculated. Concentrations of free fatty acids in renal venous plasma were usually lower than the arterial concentrations. The arteriovenous differences were statistically highly significant. The results also suggested that the degree of free fatty acid removal was proportional to the arterial concentration of this metabolite.

Free fatty acid concentration and composition in arterial blood

1962 ◽  
Vol 203 (2) ◽  
pp. 306-310 ◽  
Author(s):  
Martin E. Rothlin ◽  
Christine B. Rothlin ◽  
Vernon E. Wendt
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Free Fatty Acids ◽  
Free Fatty Acid Concentration ◽  
Arterial Blood ◽  
Arterial Concentration ◽  
The Subject ◽  
Palmitic Acids

The effect of the administration of norepinephrine, glucose and insulin, pentobarbital, and Hypertensin on the arterial concentration and composition of plasma free fatty acids (FFA) has been studied in man and dog. With a rise of the FFA concentration as produced by norepinephrine, the contribution of oleic acid to the total FFA increased, while that of stearic and palmitic acids decreased. The reverse changes in the FFA composition were observed when their arterial level fell under the influence of other agents studied. The FFA composition was dependent on the FFA concentration in arterial blood, but not on the experimental condition of the subject or animal at the time of analysis. At high FFA levels, the FFA composition approached that of depot fat.

Reaction of Free Fatty Acids with Protein in Cod Muscle Frozen and Stored at −29 C after Aging in Ice

1969 ◽  
Vol 26 (10) ◽  
pp. 2727-2736 ◽  
Author(s):  
Margaret L. Anderson ◽  
Elinor M. Ravesi
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Complex Formation ◽  
Free Fatty Acids ◽  
Phase Contrast ◽  
Reaction Rate ◽  
Frozen Storage ◽  
Phase Contrast Micrographs ◽  
Protein Extractability

Freezing and holding cod muscle in the frozen state favored the association process that involves protein–free fatty acid (FFA) complex formation and begins during aging in ice. Changes in protein extractability, in ultracentrifugal patterns of protein extracted, and in phase contrast micrographs of inextractable muscle fragments were followed in muscle that had been aged in ice to produce various contents of FFA and then frozen and held at −29 C. After 11 months, these changes, which took place largely during the first week of storage, were comparable with those that occur when the FFA are formed during frozen storage. The results were consistent with a reaction rate that was greater at −29 C than at temperatures a few degrees above 0 C.

scholarly journals Article Commentary: A Role for IR-β in the Free Fatty Acid Mediated Development of Hepatic Insulin Resistance?

2009 ◽  
Vol 2 ◽  
pp. BCI.S2996
Author(s):  
Samit Shah ◽  
Arthur G. Cox
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Free Fatty Acids ◽  
Pi3k Pathway ◽  
Hepatic Insulin Resistance ◽  
Hamster Model ◽  
High Concentrations ◽  
Nfκb Pathway

Several studies have been conducted to elucidate the role of free fatty acids (FFAs) in the pathogenesis of type 2 diabetes, but the exact molecular mechanism by which FFAs alter glucose metabolism in the liver is still not completely understood. 1 – 4 In a recent publication, Ragheb and coworkers have examined the effect of free fatty acid (FFA) treatment on insulin signaling and insulin resistance by using immunoprecipitation and immunoblotting to study the effect of high concentrations of insulin and FFAs on insulin receptor-beta (IR-β) and downstream elements in the PI3K pathway using the fructose-fed hamster model. 5 Their results clearly show that free fatty acids have an insignificant effect on IR-β and supports previous findings that FFAs lead to insulin resistance in the liver via the PKC-NFκB pathway. 2 , 3

Sign in / Sign up

Export Citation Format

Share Document