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 Date21 Oct 2024

Sponsor / Collaborator

NGM Biopharmaceuticals, Inc.

NCT05130047 / CompletedPhase 2IIT

A Randomized, Double-Blind, Placebo Controlled Trial of Aldafermin (NGM282) for Treatment of Chronic Diarrhea Due to Bile Acid Malabsorption (BAM)

This single-center, randomized, double-blind, placebo-controlled study is designed to compare effects of aldafermin, (NGM282), 1 mg, and placebo given daily by subcutaneous injection on bowel functions and hepatic synthesis and fecal excretion of bile acids in patients with diarrhea associated with bile acid malabsorption (BAM).

Start Date01 Dec 2021

Sponsor / Collaborator

Mayo Clinic

[+1]

EUCTR2019-003048-63-SE / Not yet recruitingPhase 2

A Phase 2b Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of MK-3655 in Individuals With Pre-cirrhotic Nonalcoholic Steatohepatitis.

Start Date30 Jul 2021

Sponsor / Collaborator-

100 Clinical Results associated with FGFR1 x KLB

100 Translational Medicine associated with FGFR1 x KLB

0 Patents (Medical) associated with FGFR1 x KLB

Literatures (Medical) associated with FGFR1 x KLB

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.

01 Feb 2024·American Journal of Physiology-Endocrinology and Metabolism

Vertical sleeve gastrectomy improves glucose-insulin homeostasis by enhancing β-cell function and survival via FGF15/19

Article

Author: Soares, Gabriela M ; Velloso, Lício A ; Bronczek, Gabriela A ; Marmentini, Carine ; Carneiro, Everardo M ; Vettorazzi, Jean F ; Balbo, Sandra L ; Zangerolamo, Lucas

Vertical sleeve gastrectomy (VSG) decreases insulin secretion, endoplasmic reticulum (ER) stress, and inflammation in pancreatic islets from obese mice. In addition, VSG increased fibroblast growth factor (FGF)15 circulating levels in obese mice, as well as the expression of FGF receptor 1 ( Fgfr1) and its coreceptor β-klotho ( Klb), both in pancreatic islets from VSG mice and in INS-1E β-cells treated with the serum from these mice. Serum from operated mice protects INS-1E cells from dysfunction and apoptosis, which was mediated by FGF15/19.

01 Oct 2023·Brain Research Bulletin

FGF21 prevents neuronal cell ferroptosis after spinal cord injury by activating the FGFR1/β-Klotho pathway

Article

Author: Lin, Xiaolong ; Ge, Jianfei ; Wang, Liming ; Sha, Weiping ; Tian, Shoujin ; Zhu, Yi ; Zhu, Qiancheng ; Tang, Mengjie ; Huang, Qun ; Gu, Qi ; Xu, Tianli ; Yan, Fei

Spinal cord injury (SCI) is a kind of traumatic nervous system disease caused by neuronal death, causing symptoms like sensory, motor, and autonomic nerve dysfunction. The recovery of neurological function has always been a intractable problem that has greatly distressed individuals and society. Although the involvement of iron-dependent lipid peroxidation leading to nerve cell ferroptosis in SCI progression has been reported, the underlying mechanisms remain unaddressed. Thus, this study aimed to investigate the potential of recombinant human FGF21 (rhFGF21) in inhibiting ferroptosis of nerve cells and improving limb function after SCI, along with its underlying mechanisms. In vivo animal model showed that FGFR1, p-FGFR1, and β-Klotho protein gradually increased over time after injury, reaching a peak on the third day. Moreover, rhFGF21 treatment significantly reduced ACSL4, increased GPX4 expression, reduced iron deposition, and inhibited ferroptosis. Meanwhile, rhFGF21 decreased cell apoptosis following acute spinal cord damage. In contrast, FGFR1 inhibitor PD173074 partially reversed the rhFGF21-induced therapeutic effects. Overall, this work revealed that rhFGF21 activates the FGFR1/β-Klotho pathway to decrease ferroptosis of nerve cells, suggesting that FGF21 could be a new therapeutic target for SCI neurological rehabilitation.

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