scholarly journals Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators

2021 ◽  
Vol 22 (4) ◽  
pp. 1763
Author(s):  
Manuel Grundmann ◽  
Eckhard Bender ◽  
Jens Schamberger ◽  
Frank Eitner
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Drug Targets ◽  
Current Knowledge ◽  
Receptor Site ◽  
Host Responses ◽  
Target Class ◽  
The Rich ◽  
Orthosteric Ligands ◽  
Free Fatty Acid Receptors

The physiological function of free fatty acids (FFAs) has long been regarded as indirect in terms of their activities as educts and products in metabolic pathways. The observation that FFAs can also act as signaling molecules at FFA receptors (FFARs), a family of G protein-coupled receptors (GPCRs), has changed the understanding of the interplay of metabolites and host responses. Free fatty acids of different chain lengths and saturation statuses activate FFARs as endogenous agonists via binding at the orthosteric receptor site. After FFAR deorphanization, researchers from the pharmaceutical industry as well as academia have identified several ligands targeting allosteric sites of FFARs with the aim of developing drugs to treat various diseases such as metabolic, (auto)inflammatory, infectious, endocrinological, cardiovascular, and renal disorders. GPCRs are the largest group of transmembrane proteins and constitute the most successful drug targets in medical history. To leverage the rich biology of this target class, the drug industry seeks alternative approaches to address GPCR signaling. Allosteric GPCR ligands are recognized as attractive modalities because of their auspicious pharmacological profiles compared to orthosteric ligands. While the majority of marketed GPCR drugs interact exclusively with the orthosteric binding site, allosteric mechanisms in GPCR biology stay medically underexploited, with only several allosteric ligands currently approved. This review summarizes the current knowledge on the biology of FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), FFAR4 (GPR120), and GPR84, including structural aspects of FFAR1, and discusses the molecular pharmacology of FFAR allosteric ligands as well as the opportunities and challenges in research from the perspective of drug discovery.

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.

scholarly journals Yellow Fever: Integrating Current Knowledge with Technological Innovations to Identify Strategies for Controlling a Re-Emerging Virus

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 960 ◽  
Author(s):  
Robin D.V. Kleinert ◽  
Eduardo Montoya-Diaz ◽  
Tanvi Khera ◽  
Kathrin Welsch ◽  
Birthe Tegtmeyer ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Drug Targets ◽  
Yellow Fever Virus ◽  
Current Knowledge ◽  
Hemorrhagic Fever ◽  
Structural Data ◽  
Host Responses ◽  
Effective Vaccine ◽  
Tropical Regions ◽  
Technological Advances

Yellow fever virus (YFV) represents a re-emerging zoonotic pathogen, transmitted by mosquito vectors to humans from primate reservoirs. Sporadic outbreaks of YFV occur in endemic tropical regions, causing a viral hemorrhagic fever (VHF) associated with high mortality rates. Despite a highly effective vaccine, no antiviral treatments currently exist. Therefore, YFV represents a neglected tropical disease and is chronically understudied, with many aspects of YFV biology incompletely defined including host range, host–virus interactions and correlates of host immunity and pathogenicity. In this article, we review the current state of YFV research, focusing on the viral lifecycle, host responses to infection, species tropism and the success and associated limitations of the YFV-17D vaccine. In addition, we highlight the current lack of available treatments and use publicly available sequence and structural data to assess global patterns of YFV sequence diversity and identify potential drug targets. Finally, we discuss how technological advances, including real-time epidemiological monitoring of outbreaks using next-generation sequencing and CRISPR/Cas9 modification of vector species, could be utilized in future battles against this re-emerging pathogen which continues to cause devastating disease.

GENERAL EFFECTS OF α-MELANOCYTE STIMULATING HORMONE IN THE RABBIT

1965 ◽  
Vol 48 (4) ◽  
pp. 609-618 ◽  
Author(s):  
H. K. Dyster-Aas ◽  
C. E. T. Krakau
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Serum Calcium ◽  
Calcium Level ◽  
Serum Calcium Level ◽  
Systemic Effects ◽  
List Type ◽  
Aqueous Flare ◽  
Melanocyte Stimulating Hormone ◽  
Blood Aqueous Barrier

ABSTRACT In addition to the previously described permeability disturbance in the blood aqueous barrier of the eye, measured as an increase of the aqueous flare, a series of transitory systemic effects have been recorded following the subcutaneous injection of synthetic α-MSH: marked increase of the free fatty acids in plasma, decrease in the serum calcium level, decrease in the blood pressure, increase in the skin temperature, increased frequency and diminished amplitude of respiration, presence of slow waves in the EEG. There is a correlation between the magnitude of the aqueous flare increase and the increase of free fatty acids in plasma and also between the aqueous flare and the minimum serum calcium level.

The Relationship of Fasting Free Fatty Acids, Adipose Tissue, Insulin Resistance, and Fasting Glucose Concentrations with Subsequent ß-Cell Function in Nondiabetic Subjects

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1812-P
Author(s):  
MARIA D. HURTADO ◽  
J.D. ADAMS ◽  
MARCELLO C. LAURENTI ◽  
CHIARA DALLA MAN ◽  
CLAUDIO COBELLI ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Free Fatty Acids ◽  
Cell Function ◽  
Fasting Glucose ◽  
Relationship Of ◽  
The Relationship

1010-P: Effects of MEDI0382, an Oxyntomodulin-Like Peptide with Targeted GLP-1/Glucagon Receptor Activity, on Amino Acids, Ketones, and Free Fatty Acids

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1010-P
Author(s):  
VICTORIA E. PARKER ◽  
DARREN ROBERTSON ◽  
TAO WANG ◽  
DAVID C. HORNIGOLD ◽  
MAXIMILIAN G. POSCH ◽  
...  
Keyword(s):  
Amino Acids ◽  
Fatty Acids ◽  
Free Fatty Acids ◽  
Receptor Activity ◽  
Glucagon Receptor

Alcohol intake impairs glucose counterregulation during acute insulin-induced hypoglycemia in IDDM patients. Evidence for a critical role of free fatty acids

Diabetes ◽  
1993 ◽  
Vol 42 (11) ◽  
pp. 1626-1634 ◽  
Author(s):  
A. Avogaro ◽  
P. Beltramello ◽  
L. Gnudi ◽  
A. Maran ◽  
A. Valerio ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Alcohol Intake ◽  
Critical Role

Metabolic consequences of sustained suppression of free fatty acids by acipimox in patients with NIDDM

Diabetes ◽  
1993 ◽  
Vol 42 (11) ◽  
pp. 1559-1566 ◽  
Author(s):  
C. Saloranta ◽  
M. R. Taskinen ◽  
E. Widen ◽  
M. Harkonen ◽  
A. Melander ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids
Sign in / Sign up

Export Citation Format

Share Document