Fibroblast Growth Factors for Nonalcoholic Fatty Liver Disease: Opportunities and Challenges

Abstract

Nonalcoholic fatty liver disease (NAFLD), a chronic condition associated with metabolic dysfunction and obesity, has reached epidemic proportions worldwide. Although early NAFLD can be treated with lifestyle changes, the treatment of advanced liver pathology, such as nonalcoholic steatohepatitis (NASH), remains a challenge. There are currently no FDA-approved drugs for NAFLD. Fibroblast growth factors (FGFs) play essential roles in lipid and carbohydrate metabolism and have recently emerged as promising therapeutic agents for metabolic diseases. Among them, endocrine members (FGF19 and FGF21) and classical members (FGF1 and FGF4) are key regulators of energy metabolism. FGF-based therapies have shown therapeutic benefits in patients with NAFLD, and substantial progress has recently been made in clinical trials. These FGF analogs are effective in alleviating steatosis, liver inflammation, and fibrosis. In this review, we describe the biology of four metabolism-related FGFs (FGF19, FGF21, FGF1, and FGF4) and their basic action mechanisms, and then summarize recent advances in the biopharmaceutical development of FGF-based therapies for patients with NAFLD.

Non-alcoholic fatty liver disease: Immunological mechanisms and current treatments

“…Fibroblast growth factor (FGF) based therapeutics: FGF analogs have been proposed to target steps of disease pathogenesis. FGF-21 treatments are currently in clinical development for the treatment of NASH[ 153 , 154 ] and data suggests that FGF21 is anti-fibrotic and has the potential to improve the metabolic syndrome and is effective in treating NASH. The BALANCED trial (NCT03976401) evaluated the effects of efruxifermin, a long-acting Fc-FGF21 fusion protein[ 155 ].…”

FGF19 Promotes the Proliferation and Insulin Secretion from Human Pancreatic β Cells Via the IRS1/GLUT4 Pathway

“…Beyond its primary function in bile acid regulation, FGF19 has emerged as a metabolic coordinator that interacts with various organs, including the gut, liver, brain, and white adipose tissue, to maintain overall metabolic balance [17][18][19][20]. Recent studies have provided valuable insights into the pivotal regulatory function of FGF19 in glucose and lipid metabolism, energy expenditure, and adiposity [21,22]. In mice lacking Fgf15 (the mouse ortholog of FGF19), serum glucose levels were dysregulated, hepatic glycogen was diminished, and glucose intolerance was observed, which could be restored by FGF19 administration, thus ameliorating metabolic imbalances [23].…”

NASH Drug Development: Seeing the Light at the End of the Tunnel?

“…Major therapeutic targets include lipid metabolic enzymes acetyl-CoA carboxylase (ACC) 6 and fatty acid synthase (FASN), 7 which affect liver steatosis; farnesoid X receptor (FXR) 8 which interferes with bile acid signaling; nuclear receptors peroxisome proliferator-activated receptor (PPAR), 9 and thyroid hormone receptor beta (THRb) 10 as well as antidiabetic-peptide receptors GLP-1 receptor (GLP1R), 11 glucagon receptor (GCGR) 12 and GIP receptor (GIPR), 13 which alter glucose and lipid metabolism; FGF21 and FGF19 receptors, which have pleiotropic effects on liver steatosis, inflammation and fibrosis; 14 chemokine (C-C motif) ligand 2 and 5 (CCL2/5) 15 and amine oxidase copper containing 3 (AOC3), 16 which influence inflammation; lysyl oxidase-like 2 (LOXL2), 17 which involves in fibrosis; and caspases, which are key players in apoptosis ( Fig. 2 ).…”