FGF21 protects against hepatic lipotoxicity and macrophage activation to attenuate fibrogenesis in nonalcoholic steatohepatitis
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The authors present an important study of the effects of chronic hepatic FGF21 overexpression on the development of non-alcoholic steatohepatitis (NASH) in a model of obesity and dyslipidemia, i.e. ApoE3-Leiden CETP transgenic mice fed a western diet. NASH is a major global health problem and exogenous FGF21 treatment has been explored as a therapeutic strategy. The authors find that chronic overexpression of FGF21 blocks weight gain on the western diet, and even induces some weight loss compared to the control diet. The findings are convincing and methodologically sound.
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Abstract
Analogues of the hepatokine fibroblast growth factor 21 (FGF21) are in clinical development for type 2 diabetes and nonalcoholic steatohepatitis (NASH) treatment. Although their glucose-lowering and insulin-sensitizing effects have been largely unraveled, the mechanisms by which they alleviate liver injury have only been scarcely addressed. Here, we aimed to unveil the mechanisms underlying the protective effects of FGF21 on NASH using APOE*3-Leiden.CETP mice, a well-established model for human-like metabolic diseases. Liver-specific FGF21 overexpression was achieved in mice, followed by administration of a high-fat high-cholesterol diet for 23 weeks. FGF21 prevented hepatic lipotoxicity, accompanied by activation of thermogenic tissues and attenuation of adipose tissue inflammation, improvement of hyperglycemia and hypertriglyceridemia, and upregulation of hepatic programs involved in fatty acid oxidation and cholesterol removal. Furthermore, FGF21 inhibited hepatic inflammation, as evidenced by reduced Kupffer cell (KC) activation, diminished monocyte infiltration, and lowered accumulation of monocyte-derived macrophages. Moreover, FGF21 decreased lipid- and scar-associated macrophages, which correlated with less hepatic fibrosis as demonstrated by reduced collagen accumulation. Collectively, hepatic FGF21 overexpression limits hepatic lipotoxicity, inflammation, and fibrogenesis. Mechanistically, FGF21 blocks hepatic lipid influx and accumulation through combined endocrine and autocrine signaling, respectively, which prevents KC activation and lowers the presence of lipid- and scar-associated macrophages to inhibit fibrogenesis.
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eLife assessment
The authors present an important study of the effects of chronic hepatic FGF21 overexpression on the development of non-alcoholic steatohepatitis (NASH) in a model of obesity and dyslipidemia, i.e. ApoE3-Leiden CETP transgenic mice fed a western diet. NASH is a major global health problem and exogenous FGF21 treatment has been explored as a therapeutic strategy. The authors find that chronic overexpression of FGF21 blocks weight gain on the western diet, and even induces some weight loss compared to the control diet. The findings are convincing and methodologically sound.
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Reviewer #1 (Public Review):
Rensen et al investigated the mechanisms involved in FGF21-mediated improvement in nonalcoholic steatohepatitis (NASH) and fibrosis using APOE*3-Leiden.CETP mice with AAV-8 induced overexpression of FGF21. They find that FGF21 overexpression, in the presence of an obesogenic diet, reduced hepatic lipid influx and accumulation, reduced macrophage activation and monocyte recruitment, decreased lipid- and scar-associated macrophages, and limited activation of hepatic stellate cells. Together these biological effects led to decreased steatohepatitis and fibrosis. These data delve into molecular changes underlying FGF21 phenotypic effects and add to the body of knowledge supporting the potential pharmacologic application of FGF21 in NASH.
The conclusions of the paper are mostly well supported by data, but there …
Reviewer #1 (Public Review):
Rensen et al investigated the mechanisms involved in FGF21-mediated improvement in nonalcoholic steatohepatitis (NASH) and fibrosis using APOE*3-Leiden.CETP mice with AAV-8 induced overexpression of FGF21. They find that FGF21 overexpression, in the presence of an obesogenic diet, reduced hepatic lipid influx and accumulation, reduced macrophage activation and monocyte recruitment, decreased lipid- and scar-associated macrophages, and limited activation of hepatic stellate cells. Together these biological effects led to decreased steatohepatitis and fibrosis. These data delve into molecular changes underlying FGF21 phenotypic effects and add to the body of knowledge supporting the potential pharmacologic application of FGF21 in NASH.
The conclusions of the paper are mostly well supported by data, but there are some generalizations and details that need to be further clarified or supported.
Strength:
The AAV8 expression is a powerful tool for in vivo study of potential underlying mechanisms in a disease model. Applying this method to studying FGF21 is timely and innovative given the dire need for pharmacotherapies for NASH, as well as the need to understand the potential mechanisms through which these pharmacotherapies might exert their effects.
Weakness:
The proposed endocrine and paracrine signaling, terms that are introduced for the first time in the discussion section, need more support. There is no information in the introduction section introducing this idea. More importantly, the results section does not include mechanistic data on cell binding by FGF21 in an endocrine or autocrine fashion to exert its effects as posited in the manuscript.
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Reviewer #2 (Public Review):
In the present study, Liu and colleagues set out to assess the mechanisms of the therapeutic action of FGF21 on non-alcoholic steatohepatitis in the setting of obesity and dyslipidemia. They used a liver-targeted adeno-associated virus to overexpress FGF21 as a method for chronic pharmacological-type treatment of the mice. They found that FGF21 overexpression in their mouse model prevented weight gain in high-fat, high-cholesterol (HFC) diet-fed mice, compared to the control virus on the HFC diet. In addition, many of the features of obesity, insulin resistance, and NAFLD are prevented by hepatic FGF21 overexpression in their model. The authors have performed extensive phenotyping and the results leave little doubt of the efficacy of the treatment.
My main concern with the study is the distinction between a …
Reviewer #2 (Public Review):
In the present study, Liu and colleagues set out to assess the mechanisms of the therapeutic action of FGF21 on non-alcoholic steatohepatitis in the setting of obesity and dyslipidemia. They used a liver-targeted adeno-associated virus to overexpress FGF21 as a method for chronic pharmacological-type treatment of the mice. They found that FGF21 overexpression in their mouse model prevented weight gain in high-fat, high-cholesterol (HFC) diet-fed mice, compared to the control virus on the HFC diet. In addition, many of the features of obesity, insulin resistance, and NAFLD are prevented by hepatic FGF21 overexpression in their model. The authors have performed extensive phenotyping and the results leave little doubt of the efficacy of the treatment.
My main concern with the study is the distinction between a therapeutic paradigm and the preventative paradigm employed here. Based on the body-weight curves, one might expect that real liver pathology never occurred in the FGF21-overexpressing animals. In which case, it is difficult to comment on the possibility of reversing these aspects in a therapeutic setting. This point is highly relevant to the ongoing clinical trials of FGF21 analogs for NASH that the authors have referenced.
A second point raised by the authors is the aspect of FGF21 increasing thermogenic adipose tissue activity. Their results showing FGF21-induced expression of UCP1 are not in doubt, but the fact that this increase alone is responsible for the observed phenotype is not clear. For example, FGF21 has been shown to be anorexigenic in certain models (non-human primates: Talukdar, et al. Cell Metab 2016, mini-pigs: Christoffersen, et al. Diabetes Obesity Metabolism 2019, among others). Moreover, there is evidence that some effects of FGF21-driven metabolic improvements do not require UCP1 (Samms, et al. Cell Reports 2015). Given the differences in brown fat activity and physiology between mice and humans, it would be important for the authors to either moderate their comments on the UCP1 dependence of their phenotype or provide more data to clarify to what extent their findings are UCP1-dependent (e.g. food intake in the FGF21 overexpression model and/or evidence of increased energy expenditure).
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