scholarly journals FAP finds FGF21 easy to digest

2016 ◽  
Vol 473 (9) ◽  
pp. 1125-1127 ◽  
Author(s):  
Matthew P. Gillum ◽  
Matthew J. Potthoff
Keyword(s):  
Translational Regulation ◽  
Therapeutic Strategy ◽  
Fibroblast Growth Factor 21 ◽  
Receptor Complex ◽  
Recent Issue ◽  
Carbohydrate And Lipid Metabolism ◽  
C Terminus ◽  
Biochemical Journal ◽  
Endocrine Hormone ◽  
Human Fgf21

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates carbohydrate and lipid metabolism. In humans, circulating FGF21 is inactivated by proteolytic cleavage of its C-terminus, thereby preventing signalling through a receptor complex. The mechanism for this cleavage event and the factors contributing to the post-translational regulation of FGF21 activity has previously been unknown. In a recent issue of the Biochemical Journal, Zhen et al. have identified fibroblast activation protein (FAP) as the endopeptidase responsible for this site-specific cleavage of human FGF21 (hFGF21), and propose that inhibition of FAP may be a therapeutic strategy to increase endogenous levels of active FGF21.

scholarly journals LKB1: cancer, polarity, metabolism, and now fertility

2008 ◽  
Vol 416 (1) ◽  
pp. e1-e3 ◽  
Author(s):  
Reuben J. Shaw
Keyword(s):  
Translational Regulation ◽  
Cell Metabolism ◽  
Familial Cancer ◽  
Control Cell ◽  
Serine Threonine Kinase ◽  
Lung Cancers ◽  
C Terminus ◽  
Biochemical Journal ◽  
Peutz Jeghers Syndrome ◽  
Amp Activated Protein Kinase

The LKB1 serine/threonine kinase is a tumour suppressor responsible for the inherited familial cancer disorder Peutz-Jeghers syndrome and is inactivated in a large percentage of human lung cancers. LKB1 acts a master kinase, directly phosphorylating and activating a family of 14 AMPK (AMP-activated protein kinase)-related kinases which control cell metabolism, cell growth and cell polarity. In this issue of the Biochemical Journal, Hardie and colleagues discover an alternative splice form of LKB1 that alters the C-terminus of the protein containing a few known sites of post-translational regulation. Although widely expressed, the short isoform (LKB1s) is the sole splice isoform expressed in testes, and its expression peaks at the time of spermatid maturation. Male mice lacking the LKB1s isoform have dramatic defects in spermatozoa, resulting in sterility.

From B to A: making an essential cofactor in a human parasite

2017 ◽  
Vol 474 (18) ◽  
pp. 3089-3092
Author(s):  
Naomi S. Morrissette ◽  
Celia W. Goulding
Keyword(s):  
Cytochrome C ◽  
Trypanosoma Cruzi ◽  
Cytochrome C Oxidase ◽  
Human Disease ◽  
Recent Issue ◽  
Enzyme Reactions ◽  
Human Parasite ◽  
Biochemical Journal ◽  
Eukaryotic Organisms ◽  
Subsequent Activity

Trypanosomatids are parasitic eukaryotic organisms that cause human disease. These organisms have complex lifestyles; cycling between vertebrate and insect hosts and alternating between two morphologies; a replicating form and an infective, nonreplicating one. Because trypanosomatids are one of the few organisms that do not synthesize the essential cofactor, heme, these parasites sequester the most common form, heme B, from their hosts. Once acquired, the parasites derivatize heme B to heme A by two sequential enzyme reactions. Although heme C is found in many cytochrome c and c1 proteins, heme A is the cofactor of only one known protein, cytochrome c oxidase (CcO). In a recent issue of the Biochemical Journal, Merli et al. [Biochem. J. (2017) 474, 2315–2332] demonstrate that the final step in the synthesis of heme A by heme A synthase (TcCox15) and the subsequent activity of CcO are essential for infectivity and replication of Trypanosoma cruzi.

FIBROBLAST GROWTH FACTOR 21 FROM THE PERSPECTIVE OF A PROMISING MARKER OF METABOLIC DISORDERS AND PREMATURE AGING IN POLYMORBID CARDIOVASCULAR PATHOLOGY IN YOUNG AND MIDDLE-AGED PEOPLE

2020 ◽  
Vol 4 (2) ◽  
pp. 1002-1005
Author(s):  
G.A. Proshchai ◽  
◽  
S.V. Dudarenko ◽  
A.S. Partcerniak ◽  
E.Yu. Zagarskikh ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Disorders ◽  
Premature Aging ◽  
Fibroblast Growth Factor 21 ◽  
Control Group ◽  
Middle Aged ◽  
Cardiovascular Pathology ◽  
Aged People ◽  
Carbohydrate And Lipid Metabolism

Objective: To evaluate the possibility of using fibroblast growth factor 21 (FGF 21) as a marker of metabolic disorders and premature aging in polymorbid cardiovascular pathology. Research methods: 199 men aged 35-55 years who were stratified into 3 groups were examined: group A - 117 patients with type 2 diabetes mellitus (type 2 diabetes), polymorbid cardiovascular disease (PCVD), obesity, androgen deficiency and anxiety-depressive disorders (ADD); group B - 55 patients with PCVD, obesity and ADD; group C - control group (n = 27). The examination of patients included a laboratory study of the level of FGF 21, indicators of carbohydrate and lipid metabolism, hormonal status, as well as daily monitoring of blood pressure and ECG. Results and conclusions. When compared with the control group, the level of FGF 21 was 3 times higher in the presence of type 2 diabetes. The most intense increase in FGF 21 levels was observed in groups of patients with several diseases. An increase in the level of FGF 21 in young and middle-aged people is probably due to a compensatory reaction to the existing androgen deficiency, disorders of carbohydrate and lipid metabolism. Strong correlations between FGF 21 and glucose, HDL cholesterol, total testosterone, ALT, and SBP during the day allow FGF 21 to be considered an early marker of cardiovascular disease and premature aging (PA) in young and middle-aged people

ESCRT-III on endosomes: new functions, new activation pathway

2016 ◽  
Vol 473 (2) ◽  
pp. e5-e8 ◽  
Author(s):  
Philip Woodman
Keyword(s):  
Mhc Class I ◽  
Protein Tyrosine Phosphatase ◽  
Protein Complexes ◽  
Tyrosine Phosphatase ◽  
Multivesicular Body ◽  
Class I ◽  
Recent Issue ◽  
Endosomal Sorting ◽  
Histocompatibility Complex ◽  
Biochemical Journal

The multivesicular body (MVB) pathway sorts ubiquitinated membrane cargo to intraluminal vesicles (ILVs) within the endosome, en route to the lysosomal lumen. The pathway involves the sequential action of conserved protein complexes [endosomal sorting complexes required for transport (ESCRTs)], culminating in the activation by ESCRT-II of ESCRT-III, a membrane-sculpting complex. Although this linear pathway of ESCRT activation is widely accepted, a study by Luzio and colleagues in a recent issue of the Biochemical Journal suggests that there is greater complexity in ESCRT-III activation, at least for some MVB cargoes. They show that ubiquitin-dependent sorting of major histocompatibility complex (MHC) class I to the MVB requires the central ESCRT-III complex but does not involve either ESCRT-II or functional links between ESCRT-II and ESCRT-III. Instead, they propose that MHC class I utilizes histidine-domain protein tyrosine phosphatase (HD-PTP), a non-canonical ESCRT interactor, to promote ESCRT-III activation.

14-3-3 proteins are promising LRRK2 interactors

2010 ◽  
Vol 430 (3) ◽  
pp. e5-e6 ◽  
Author(s):  
Iakov N. Rudenko ◽  
Mark R. Cookson
Keyword(s):  
Regulatory Mechanism ◽  
Cell Signalling ◽  
Regulatory Proteins ◽  
Protein Protein Interaction ◽  
Catalytic Domains ◽  
C Terminus ◽  
Disease Mutations ◽  
Biochemical Journal ◽  
Complex Protein ◽  
Interaction Domains

Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most common cause of familial PD (Parkinson’s disease). Mutations that cause PD are found in either the GTPase or kinase domains of LRRK2 or an intervening sequence called the COR [C-terminus of ROC (Ras of complex proteins)] domain. As well as the two catalytic domains, LRRK2 possesses several protein–protein interaction domains, but their function and the proteins with which they interact are poorly understood. In this issue of the Biochemical Journal, Nichols et al. study the interaction of the N-terminal region of LRRK2 with 14-3-3 proteins, regulatory proteins that often bind to phosphorylated regions of components of cell signalling pathways. Using a combination of techniques, Nichols et al. have identified two residues (Ser910 and Ser935) that are critically responsible for 14-3-3 binding. The interaction of LRRK2 with 14-3-3 proteins can prevent dephosphorylation of Ser910/Ser935 and stabilize LRRK2 structure, perhaps by influencing the dimerization of LRRK2. The ability to interact with 14-3-3 correlates with the pattern of intracellular LRRK2 distribution. Collectively, these new results identify a potentially important regulatory mechanism of this complex protein and might provide ways to think about therapeutic opportunities for PD.

scholarly journals FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest

2018 ◽  
Author(s):  
Susanna Søberg ◽  
Emilie S. Andersen ◽  
Niels B. Dalgaard ◽  
Ida Jarlhelt ◽  
Nina L. Hansen ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Binge Drinking ◽  
Alcohol Intake ◽  
Liver Stiffness ◽  
Emotional Responses ◽  
Alcohol Ingestion ◽  
Daily Injection ◽  
Fibroblast Growth Factor 21 ◽  
Excessive Alcohol Consumption ◽  
Human Fgf21

ABSTRACTObjectiveExcessive alcohol consumption is a leading cause of global morbidity and mortality. However, knowledge of the biological factors that influence adlibitumalcohol intake may be incomplete. Two large studies recently linked variants in theKLBlocus with levels of alcohol intake in humans.KLBencodes ß-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and humanFgf21variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active plasma FGF21 (FGF21 (1-181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain.MethodsWe recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1-181) measurement in plasma. In addition, we measured circulating FGF21 (1-181) levels, liver stiffness, triglyceride, and other metabolic parameters in three healthy Danish men before and after consuming an average of 22.6 beers/person/day (4.4 g/kg/day of ethanol) for three days during Oktoberfest 2017 in Munich, Germany. We further correlated fasting FGF21 (1-181) levels in 49 healthy, non-alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on adlibitumalcohol intake in mice.ResultsWe show that alcohol ingestion (25.3 grams or ~2.5 standard drinks) acutely increases plasma levels of FGF21 (1-181) 3.4-fold in fasting humans. We also find that binge drinking for three days at Oktoberfest is associated with a 2.1-fold increase in baseline FGF21 (1-181) levels, in contrast to minor deteriorations in metabolic and hepatic biomarkers. However, basal FGF21 (1-181) levels were not correlated with differences in alcohol-related behaviors, emotional responses, or problems in our non-alcoholic subjects. Finally, we show that once-daily injection of recombinant human FGF21 reduces adlibitumalcohol intake by 21% in mice.ConclusionsFGF21 (1-181) is markedly increased in circulation by both acute and sub-chronic alcohol intake in humans, and reduces alcohol intake in mice. These observations are consistent with a role for FGF21 as an endocrine inhibitor of alcohol appetite in humans.

scholarly journals Generation of Affinity Purified Antibody Reagents for Specific Determination of Efruxifermin in Biological Matrices

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A288-A288
Author(s):  
Adam S Kinne ◽  
Sanofar J Abdeen ◽  
Elijah S Parmer ◽  
Jennifer A Thystrup ◽  
Erik J Tillman ◽  
...  
Keyword(s):  
Amino Acid ◽  
Half Life ◽  
Clinical Development ◽  
Amino Acid Sequences ◽  
Fibroblast Growth Factor 21 ◽  
Biological Matrices ◽  
Specific Determination ◽  
Human Igg1 ◽  
Human Fgf21

Abstract Efruxifermin (EFX) is a novel Fc-fusion analog of human fibroblast growth factor 21 (FGF21), currently in clinical development as a potential treatment for non-alcoholic steatohepatitis (NASH). Each molecule of EFX consists of two modified FGF21 molecules, each attached at their N-termini to a human IgG1 Fc domain by a short polyglycine-serine linker. The FGF21 moiety of EFX incorporates three amino acid substitutions (L98R, P171G, and A180E relative to native FGF21). Two of these are proximal to the C-terminus (P171G and A180E), and reduce cleavage and inactivation by an endogenous protease, fibroblast activation protein (FAP), thereby prolonging its half-life. Fusion to human IgG1 Fc domain further extends circulating half-life, enabling once-weekly subcutaneous dosing. Accordingly, to support on-going clinical development of EFX, a specific assay is needed to distinguish intact EFX from both endogenous FGF21 and any in vivo biotransformation products of EFX that display reduced pharmacology. To maximize the antigenicity of EFX, FGF21 amino acid sequences were compared across species. Based on this, an antibody generation campaign was initiated in both rabbits and chickens. Comparison of titer responses against EFX and human FGF21 suggested that antisera from chickens was superior to rabbit antisera. Following a scaled-up, 12-week antibody campaign, antisera were purified by a combination of batch and column chromatographic procedures. By exploiting differences in structure and amino acid sequence of EFX relative to human FGF21, a purification strategy was designed to isolate chicken antibodies with increased specificity for EFX unique sequences. This reagent is being used as a capture antibody in the development of a noncompetitive ECLIA employing chemiluminescence detection. Presently, a number of different antibodies are being evaluated for potential pairing with the specific capture. We conclude that application of affinity purified chicken anti-EFX IgY will enable sensitive and specific determination of EFX in biological matrices with decreased cross-reactivity from endogenous hFGF21 and EFX metabolites.

scholarly journals Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis

2018 ◽  
Vol 38 (1) ◽  
pp. 173-196 ◽  
Author(s):  
Lucas D. BonDurant ◽  
Matthew J. Potthoff
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Therapeutic Potential ◽  
Nutrient Sensing ◽  
The Body ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Metabolic Homeostasis ◽  
Endocrine Hormone ◽  
Endocrine Factor

Fibroblast growth factor 21 (FGF21) is an endocrine hormone derived from the liver that exerts pleiotropic effects on the body to maintain overall metabolic homeostasis. During the past decade, there has been an enormous effort made to understand the physiological roles of FGF21 in regulating metabolism and to identify the mechanism for its potent pharmacological effects to reverse diabetes and obesity. Through both human and rodent studies, it is now evident that FGF21 levels are dynamically regulated by nutrient sensing, and consequently FGF21 functions as a critical regulator of nutrient homeostasis. In addition, recent studies using new genetic and molecular tools have provided critical insight into the actions of this endocrine factor. This review examines the numerous functions of FGF21 and highlights the therapeutic potential of FGF21-targeted pathways for treating metabolic disease.

Metformin and respiratory chain complex I: the last piece of the puzzle?

2014 ◽  
Vol 463 (3) ◽  
pp. e3-e5 ◽  
Author(s):  
Eric Fontaine
Keyword(s):  
Complex I ◽  
Chain Complex ◽  
Recent Issue ◽  
Intact Cells ◽  
Biochemical Journal ◽  
The Difference ◽  
High Concentrations ◽  
Complex I Activity ◽  
First Time

Metformin is the most widely prescribed drug used to treat patients affected by Type 2 diabetes. Metformin has also been shown to prevent some forms of cell death; however, evidence suggests that it may have anti-neoplastic properties. All of these effects have been attributed to complex I inhibition, but the mechanism by which metformin leads to complex I inhibition is not fully understood. Although it has been reported that the incubation of functionally isolated complex I in the presence of high concentrations of metformin led to its inhibition, much lower concentrations of metformin have been shown to inhibit complex I in intact cells. In a recent issue of the Biochemical Journal, Bridges, Jones, Pollak and Hirst [(2014) Biochem. J. 462, 475–487] studied for the first time the effect of metformin on purified complex I. They report that millimolar concentrations of metformin directly inhibit complex I activity in a non-competitive manner. They also specify that the binding of metformin to complex I depends on its conformation. To explain the difference in concentration required to inhibit complex I in intact cells and on isolated enzyme, Bridges et al. (2014) propose that metformin concentrates within mitochondria in intact cells. Albeit theoretically plausible, this attractive hypothesis is not directly tested by Bridges et al. (2014) Moreover, although sparse, the current literature does not support this hypothesis.

Phosphorylation of Argonaute proteins: regulating gene regulators

2008 ◽  
Vol 413 (3) ◽  
pp. e7-e9 ◽  
Author(s):  
Sabine Rüdel ◽  
Gunter Meister
Keyword(s):  
Gene Silencing ◽  
Translational Regulation ◽  
Mitogen Activated Protein Kinase ◽  
Rna Turnover ◽  
Processing Bodies ◽  
P Bodies ◽  
Biochemical Journal ◽  
Mitogen Activated Protein ◽  
Silencing Pathways ◽  
Protein Kinase Signalling

Members of the Ago (Argonaute) protein family are the mediators of small RNA-guided gene-silencing pathways including RNAi (RNA interference), translational regulation by miRNAs (microRNAs) and transcriptional silencing. Recent findings by Zeng et al. in this issue of the Biochemical Journal demonstrate that Ago proteins are post-translationally modified by phosphorylation of Ser387. Mutating Ser387 to alanine leads to reduced localization of human Ago2 to cytoplasmic P-bodies (processing bodies), cellular sites where RNA turnover and, at least in part, miRNA-guided gene regulation occurs. Zeng et al. further show that a member of the MAPK (mitogen-activated protein kinase) signalling pathway phosphorylates Ago2 at Ser387, suggesting that Ago2-mediated gene silencing might be linked to distinct signalling pathways.

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