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Last update 23 Jan 2025

KLB

Last update 23 Jan 2025

Basic Info

Synonyms

b-Klotho, Beta-klotho, BetaKlotho

+ [4]

Introduction

Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. Probably inactive as a glycosidase. Increases the ability of FGFR1 and FGFR4 to bind FGF21 (By similarity).

Drugs associated with KLB

Aldafermin

Target

FGFR1 x FGFR4 x KLB

Mechanism

FGFR1 stimulants [+2]

Active Org.

NGM Biopharmaceuticals, Inc.

Originator Org.

NGM Biopharmaceuticals, Inc.

Active Indication

Cholangitis, Sclerosing [+6]

Inactive Indication

Constipation - functional [+4]

Drug Highest PhasePhase 2/3

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

NGM-313

Target

FGFR1 x KLB

Mechanism

FGFR1 stimulants [+1]

Active Org.

Biotechnologines Farmacijos Centras [+2]

Originator Org.

NGM Biopharmaceuticals, Inc.

Active Indication

Nonalcoholic Steatohepatitis [+1]

Inactive Indication

Insulin Resistance [+1]

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Anti-FGFR1/KLB MAb(Genentech)

Target

FGFR1 x KLB

Mechanism

FGFR1 stimulants [+1]

Active Org.

Genentech, Inc.

Originator Org.

Genentech, Inc.

Active Indication

Nonalcoholic Steatohepatitis

Inactive Indication-

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with KLB

NCT06654726

/ Not yet recruitingPhase 2/3

A Phase 2b/3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Safety, and Tolerability of Aldafermin in Subjects With Primary Sclerosing Cholangitis (ALPINE-PSC).

A multi-center evaluation of aldafermin in a randomized, double-blind, placebo-controlled study in subjects with Primary Sclerosing Cholangitis.

Start Date01 May 2025

Sponsor / Collaborator

NGM Biopharmaceuticals, Inc.

NCT06564467

/ Enrolling by invitationPhase 1

A Phase І, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of JMT202 Injection in Chinese Healthy Participants

This is a randomized, double-blind, placebo-controlled, single ascending dose (SAD) study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneously Administered JMT202 in Healthy Participants.

Start Date23 Jul 2024

Sponsor / Collaborator

Shanghai JMT Biological Technology Co Ltd

CTR20242512

/ RecruitingPhase 1

一项单中心、随机、双盲、安慰剂对照、单次剂量递增、评价JMT202注射液在中国健康受试者中的安全性、耐受性、药代动力学和药效动力学特征的I期临床试验

[Translation] A single-center, randomized, double-blind, placebo-controlled, single-dose escalation phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of JMT202 injection in healthy Chinese subjects

主要目的：评估在中国健康受试者中单次皮下注射JMT202注射液的安全性和耐受性次要目的：评估在中国健康受试者中单次皮下注射JMT202注射液后的药代动力学特征、免疫原性和药效动力学特征

[Translation]

Primary objective: To evaluate the safety and tolerability of a single subcutaneous injection of JMT202 injection in healthy Chinese subjects Secondary objective: To evaluate the pharmacokinetic, immunogenicity and pharmacodynamic characteristics of JMT202 injection after a single subcutaneous injection in healthy Chinese subjects

Start Date23 Jul 2024

Sponsor / Collaborator

Shanghai JMT Biological Technology Co Ltd

100 Clinical Results associated with KLB

100 Translational Medicine associated with KLB

0 Patents (Medical) associated with KLB

372

Literatures (Medical) associated with KLB

01 Feb 2025·International Immunopharmacology

Fibroblast growth factor 21 alleviated atopic march by inhibiting the differentiation of type 2 helper T cells

Article

Author: Zhao, Tianqi ; Li, Xinyu ; Ren, Guiping ; Liu, Peijing ; Wang, Dan ; Cao, Weiyue ; Li, Zhitong ; Zou, Yimeng ; Bai, Lin ; Han, Jiachi ; Wu, Qing

BACKGROUNDThe blood FGF21 expression has been previously suggested to increase in patients developing atopic dermatitis (AD) and asthma. However, its impact on atopic march is rarely analyzed. The present work focused on investigating the role of Fibroblast Growth Factor 21(FGF21) in atopic march mice and its underlying mechanisms.METHODSThe models were induced with Diisononyl phthalate (DINP) and OVA in wild-type C57BL/6 and FGF21^-/- mice. RAW264.7 cells were induced by LPS with/without FGF21 or KLB-SiRNA for in vitro analyses.RESULTSThe data indicated that there were more severe allergic reactions including IgE levels and the proportion of mast cells in the blood of FGF21^-/- mice in relative to WT model mice during the progression from AD to asthma. However, exogenous administration of FGF21 inhibited allergies. In this study, we reported that FGF21 mitigated AD-like lesions and Th1/2 or Th17/Treg cell imbalance in AD mice, and significantly decreased TSLP, IL-33, IL-4, IL-5, IL-13 and IL-17A expression on skin. During the asthma phase, FGF21 improved airway remodeling by downgrading inflammatory factors IL-4, IL-5, IL-13 and IL-17A; fibrotic markers α-SMA and Collagen I; and oxidative products MDA and ROS in wild-type model mice. Compared with WT model mice, the adverse consequences were aggravated in FGF21^-/- asthmatic mice. From the mechanistic perspective, FGF21 suppressed NF-κB/NLRP3, TGF-β1/Smad3 and JNK signaling pathways and increased Nrf2 expression in vivo and in vitro. In addition, β-Klotho knockdown attenuated the ameliorative impact of FGF21 on cellular damage. Blocking AMPKα in the LPS-treated RAW264.7 cells inhibited the reduction of FGF21 and the phosphorylation of JNK.CONCLUSIONSTo conclude, FGF21 alleviated atopic march by inhibiting Th2/17 immune response, and reduced airway remodeling by regulating NF-κB/NLRP3, TGF-β1/Smad3 and AMPKα/JNK pathways. Moreover, this study provides a rationale and novel ideas for applying FGF21 in treating AD and asthma.

01 Feb 2025·International Journal of Biological Macromolecules

Site-specific analysis and functional characterization of N-linked glycosylation for β-Klotho protein

Article

Author: Lin, Ying ; Xu, Aimin ; Yi, Xinyao ; Abulimiti, Xiayidan ; Yu, Jiasui ; Jin, Leigang ; Geng, Leiluo

β-Klotho (KLB), a type I transmembrane protein, serves as an obligate co-receptor determining the tissue-specific actions of endocrine fibroblast growth factors (FGFs). Despite accumulative evidence suggesting the occurrence of N-glycosylation in the KLB protein, the precise N-glycosites, glycoforms, and the impacts of N-glycosylation on the expression and function of the KLB protein remain unexplored. Employing a mass spectrometry-based approach, a total of 12 N-glycosites displaying heterogeneous site occupancy and glycoforms were identified within the extracellular region of the recombinant human KLB protein. Molecular simulation revealed negligible impact of these N-glycans on the overall structure of the KLB protein. However, both pharmacological inhibition of N-glycosylation and mutagenesis targeting N-glycosites reduced mature KLB protein content without impacting KLB mRNA synthesis in cells, underscoring the critical role of N-glycosylation in maintaining the stability of the KLB protein. Further studies revealed that the underglycosylated KLB mutant underwent rapid degradation via both lysosomal and proteasomal pathways and was unable to be efficiently trafficked to the plasma membrane, leading to impaired FGF21 signaling transduction. Collectively, multisite N-glycosylation is essential for the stability and cell surface localization of the KLB protein, representing a novel modulatory mechanism of endocrine FGF signaling.

01 Nov 2024·Free Radical Biology and Medicine

Caffeic acid ameliorates metabolic dysfunction-associated steatotic liver disease via alleviating oxidative damage and lipid accumulation in hepatocytes through activating Nrf2 via targeting Keap1

Article

Author: Gu, Xinnan ; Huang, Zhenlin ; Ouyang, Hao ; Lu, Bin ; Li, Jian ; Ji, Lili ; Zhang, Jinyu ; Dong, Shiyuan

Metabolic-associated steatotic liver disease (MASLD), known as non-alcoholic fatty liver disease (NAFLD) in the past, encompasses a range of liver pathological conditions marked by the excessive lipid accumulation. Consumption of coffee is closely associated with the reduced risk of MASLD. Caffeic acid (CA), a key active ingredient in coffee, exhibits notable hepatoprotective properties. This study aims to investigate the improvement of CA on MASLD and the engaged mechanism. Mice underwent a 12-week high-fat diet (HFD) regimen to induce MASLD, and liver pathology was assessed using hematoxylin-eosin (H&E) and oil red O (ORO) staining. Hepatic inflammation was evaluated by F4/80 and Ly6G immunohistochemistry (IHC) and myeloperoxidase (MPO) measurement. Pathways and transcription factors relevant to MASLD were analyzed by using microarray data from patients' livers. Oxidative damage was evaluated by detecting reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD). Co-immunoprecipitation (CoIP), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) were used to validate the binding between CA and its target protein. CA significantly alleviated liver damage, steatosis and inflammatory injury, and reduced the elevated NAFLD activity score (NAS) in HFD-fed mice. Clinical data indicate that fatty acid metabolism and ROS generation are pivotal in MASLD progression. CA increased the expression of fibroblast growth factor 21 (FGF21), FGF receptor 1 (FGFR1) and β-Klotho (KLB), and promoted fatty acid consumption. Additionally, CA mitigated oxidative stress injury and activated nuclear factor erythroid 2-related factor-2 (Nrf2). In primary hepatocytes isolated from Nrf2 knockout mice, CA's promotion on FGF21 release and inhibition on oxidative stress and lipotoxicity was disappeared. CA could directly bind to kelch-like ECH-associated protein 1 (Keap1) that is an Nrf2 inhibitor protein. This study suggests that CA alleviates MASLD by reducing hepatic lipid accumulation, lipotoxicity and oxidative damage through activating Nrf2 via binding to Keap1.

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KLB

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