Abstract
The rising global prevalence of obesity, metabolic syndrome, and type 2 diabetes has driven a sharp increase in non-alcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in the liver. Approximately one-sixth of the NAFLD population progresses to non-alcoholic steatohepatitis (NASH) with liver inflammation, hepatocyte injury and cell death, liver fibrosis and cirrhosis. NASH is one of the leading causes of liver transplant, and an increasingly common cause of hepatocellular carcinoma (HCC), underscoring the need for intervention. The complex pathophysiology of NASH, and a predicted prevalence of 3–5% of the adult population worldwide, has prompted drug development programs aimed at multiple targets across all stages of the disease. Currently, there are no approved therapeutics. Liver-related morbidity and mortality are highest in more advanced fibrotic NASH, which has led to an early focus on anti-fibrotic approaches to prevent progression to cirrhosis and HCC. Due to limited clinical efficacy, anti-fibrotic approaches have been superseded by mechanisms that target the underlying driver of NASH pathogenesis, namely steatosis, which drives hepatocyte injury and downstream inflammation and fibrosis. Among this wave of therapeutic mechanisms targeting the underlying pathogenesis of NASH, the hormone fibroblast growth factor 21 (FGF21) holds considerable promise; it decreases liver fat and hepatocyte injury while suppressing inflammation and fibrosis across multiple preclinical studies. In this review, we summarize preclinical and clinical data from studies with FGF21 and FGF21 analogs, in the context of the pathophysiology of NASH and underlying metabolic diseases.
Highlights
A marked rise in the global prevalence of obesity and associated metabolic pathologies has been observed over the past 30 years [1]
Whereas heparan sulfate (HS) in extracellular matrix serves as a coreceptor for autocrine and paracrine fibroblast growth factor (FGF), the endocrine FGFs rely on high-affinity interactions with either aKlotho (FGF23) or b-Klotho (FGF19 and fibroblast growth factor 21 (FGF21)) for recruitment and localization to the cell surface, where they engage canonical FGF
This review examines the unique physiology of FGF21 signaling at the cellular, tissue, and whole-body level, presenting preclinical and clinical evidence that FGF21-based therapeutics exert a broad set of metabolic actions and suppress inflammation and fibrosis
Summary
A marked rise in the global prevalence of obesity and associated metabolic pathologies has been observed over the past 30 years [1]. While the shift to address the underlying drivers of NASH holds promise, many of the mechanisms under investigation are limited to the liver as their site of action, because of safety constraints arising from systemic exposure (Table 1) As a consequence, these mechanisms have not improved whole-body metabolism, and in some cases have been associated with adverse effects such as increases in serum lowdensity lipoprotein (LDL)-cholesterol [30,31,32], serum triglycerides [33, 34], and body weight [35, 36]. Whereas HS in extracellular matrix serves as a coreceptor for autocrine and paracrine FGFs, the endocrine FGFs rely on high-affinity interactions with either aKlotho (FGF23) or b-Klotho (FGF19 and FGF21) for recruitment and localization to the cell surface, where they engage canonical FGF
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