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.

Keywords: FGF-based therapeutics; fibroblast growth factors; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis.

Figure 1

The rationale for fibroblast growth factors (FGFs) in the treatment of nonalcoholic fatty liver disease (NAFLD). FGF19 usually binds to the FGFR1c or FGFR4/β-Klotho complex to enhance lipid metabolism that can alleviate NAFLD. FGF19 inhibits the orphan nuclear receptor small heterodimeric partner (SHP)-dependent cholesterol 7α hydroxylase (CYP7A1) to prevent BA-induced liver injury in NASH. For glycometabolism, FGF19 inhibits gluconeogenesis by suppressing the cAMP response element-binding protein (CREB)/peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) signaling cascade. Meanwhile, in FGF19 transgenic mice, it was observed that FGF19 could transform normal hepatocytes into malignant cells via IL-6 by activating the STAT-3 pathway. FGF21 usually recruits β-Klotho and FGFRs (FGFR1c, FGFR2c, or FGFR3c) as coreceptors for activation, to reduce lipid deposition in hepatocytes in a non-insulin way, and the FGF21 receptor agonists can inhibit liver inflammation, fat content, and liver fibrosis in the in vitro and in vivo models of liver fibrosis and NASH. Physiological doses of FGF21 can reduce the body weight, and fat content can also alleviate insulin resistance, hyperglycemia, and dyslipidemia. In the NASH mice model, the administration of recombinant FGF1 (rFGF1) ameliorated liver inflammation and hepatocyte injury, and FGF1 normalized the blood glucose levels of both gene- and diet-induced obese mice. FGF4 is also essential in regulating glucose and lipid metabolism, as well as maintaining systemic metabolic homeostasis, which can ameliorate insulin resistance and inhibit the infiltration and the development of inflammation. FGF4 acts directly on macrophages to block inflammatory responses in the liver and adipose tissue. rFGF4^ΔNT, a non-mitotic rFGF4 analog, can have a significant protective effect on NASH through an AMPK-dependent signaling pathway.