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Research Perspectives on the Regulation and Physiological Functions of FGF21 and its Association with NAFLD.

Inagaki T - Front Endocrinol (Lausanne) (2015)

Bottom Line: Various transcription factors induce FGF21 expression in the liver, which indicates that FGF21 is a mediator of multiple environmental cues.High serum levels of FGF21 are associated with NAFLD and its risk factors, such as endoplasmic reticulum stress and chronic inflammation.In this review, the research perspectives of FGF21 and therapeutic potencies of FGF21 as a modulator of NAFLD are summarized.

View Article: PubMed Central - PubMed

Affiliation: Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo , Tokyo , Japan.

ABSTRACT
Fibroblast growth factor 21 (FGF21) is a metabolic hormone primarily secreted from the liver and functions in multiple tissues. Various transcription factors induce FGF21 expression in the liver, which indicates that FGF21 is a mediator of multiple environmental cues. FGF21 alters metabolism under starvation conditions, protects the body from energy depletion, and extends life span. Pharmacological administration of FGF21 alleviates dyslipidemia and induces weight loss in obese animals. In addition to the well-studied functions of FG21, several lines of recent evidence indicate a possible link between FGF21 and non-alcoholic fatty liver disease (NAFLD). High serum levels of FGF21 are associated with NAFLD and its risk factors, such as endoplasmic reticulum stress and chronic inflammation. In addition, FGF21 alleviates the major risk factors of NAFLD, including obesity, dyslipidemia, and insulin insensitivity. Thus, FGF21 is a potential drug candidate for diseases, such as NAFLD, dyslipidemia, and type 2 diabetes. In this review, the research perspectives of FGF21 and therapeutic potencies of FGF21 as a modulator of NAFLD are summarized.

No MeSH data available.


Related in: MedlinePlus

Regulations and functions of FGF21 signal representing a possible link between FGF21, non-alcoholic fatty liver disease, endoplasmic reticulum stress, and chronic inflammation in the liver. FGF21 is expressed in the liver, pancreas, adipose tissue, and muscle in response to various environmental cues. Several recent evidences indicate that hepatic FGF21 expression is also regulated by endoplasmic reticulum stress, chronic inflammation, and epigenetics, all of which are correlated with the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Plasma FGF21 is primarily secreted from the liver and acts in both peripheral organs and the central nervous system as a regulator of multiple biological contexts that improve NAFLD, obesity, dyslipidemia, and insulin insensitivity.
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Figure 1: Regulations and functions of FGF21 signal representing a possible link between FGF21, non-alcoholic fatty liver disease, endoplasmic reticulum stress, and chronic inflammation in the liver. FGF21 is expressed in the liver, pancreas, adipose tissue, and muscle in response to various environmental cues. Several recent evidences indicate that hepatic FGF21 expression is also regulated by endoplasmic reticulum stress, chronic inflammation, and epigenetics, all of which are correlated with the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Plasma FGF21 is primarily secreted from the liver and acts in both peripheral organs and the central nervous system as a regulator of multiple biological contexts that improve NAFLD, obesity, dyslipidemia, and insulin insensitivity.

Mentions: Fibroblast growth factor 21 gene transcription in the liver is regulated by nuclear receptor peroxisome proliferator-activated receptor (PPAR) α, which plays critical roles in fasting response (Figure 1) (6–8). Under the regulation of PPARα, hepatic FGF21 mRNA is highly expressed (~20-fold) in fasting mice. Other reports have shown that the hepatic expression of FGF21 is also regulated positively or negatively by glucocorticoid receptor (GR) (9), activating transcription factor 4 (ATF4) (10–13), cAMP-responsive element-binding protein H (CREBH) (14), carbohydrate response element-binding protein (ChREBP) (15), PPARγ (16, 17), farnesoid X receptor (FXR) (18), and liver X receptor (LXR) (19, 20) under various conditions (Figure 1) [reviewed in Ref. (21)]. In skeletal muscle, the expression of FGF21 was reported to be regulated by ATF4 under the conditions of mitochondrial dysfunction (12) and by PI3K–AKT signaling pathway (22). In brown adipose tissue (BAT), FGF21 is regulated by ATF2 (23), while in WAT, it is regulated by PPARγ (24). These known regulatory pathways indicate diverse FGF21 functions under the conditions, such as depletion of energy sources, ER stress, mitochondrial dysfunction, and on exposure to cold environment. This review will not only focus on the well-studied functions of FGF21 in glucose and lipid metabolism but also discuss current reports that suggest a possible link between FGF21 and fatty liver disease, ER stress or chronic inflammation to present research perspectives into the novel FGF21 functions in this broad and developing area of research.


Research Perspectives on the Regulation and Physiological Functions of FGF21 and its Association with NAFLD.

Inagaki T - Front Endocrinol (Lausanne) (2015)

Regulations and functions of FGF21 signal representing a possible link between FGF21, non-alcoholic fatty liver disease, endoplasmic reticulum stress, and chronic inflammation in the liver. FGF21 is expressed in the liver, pancreas, adipose tissue, and muscle in response to various environmental cues. Several recent evidences indicate that hepatic FGF21 expression is also regulated by endoplasmic reticulum stress, chronic inflammation, and epigenetics, all of which are correlated with the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Plasma FGF21 is primarily secreted from the liver and acts in both peripheral organs and the central nervous system as a regulator of multiple biological contexts that improve NAFLD, obesity, dyslipidemia, and insulin insensitivity.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4585294&req=5

Figure 1: Regulations and functions of FGF21 signal representing a possible link between FGF21, non-alcoholic fatty liver disease, endoplasmic reticulum stress, and chronic inflammation in the liver. FGF21 is expressed in the liver, pancreas, adipose tissue, and muscle in response to various environmental cues. Several recent evidences indicate that hepatic FGF21 expression is also regulated by endoplasmic reticulum stress, chronic inflammation, and epigenetics, all of which are correlated with the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Plasma FGF21 is primarily secreted from the liver and acts in both peripheral organs and the central nervous system as a regulator of multiple biological contexts that improve NAFLD, obesity, dyslipidemia, and insulin insensitivity.
Mentions: Fibroblast growth factor 21 gene transcription in the liver is regulated by nuclear receptor peroxisome proliferator-activated receptor (PPAR) α, which plays critical roles in fasting response (Figure 1) (6–8). Under the regulation of PPARα, hepatic FGF21 mRNA is highly expressed (~20-fold) in fasting mice. Other reports have shown that the hepatic expression of FGF21 is also regulated positively or negatively by glucocorticoid receptor (GR) (9), activating transcription factor 4 (ATF4) (10–13), cAMP-responsive element-binding protein H (CREBH) (14), carbohydrate response element-binding protein (ChREBP) (15), PPARγ (16, 17), farnesoid X receptor (FXR) (18), and liver X receptor (LXR) (19, 20) under various conditions (Figure 1) [reviewed in Ref. (21)]. In skeletal muscle, the expression of FGF21 was reported to be regulated by ATF4 under the conditions of mitochondrial dysfunction (12) and by PI3K–AKT signaling pathway (22). In brown adipose tissue (BAT), FGF21 is regulated by ATF2 (23), while in WAT, it is regulated by PPARγ (24). These known regulatory pathways indicate diverse FGF21 functions under the conditions, such as depletion of energy sources, ER stress, mitochondrial dysfunction, and on exposure to cold environment. This review will not only focus on the well-studied functions of FGF21 in glucose and lipid metabolism but also discuss current reports that suggest a possible link between FGF21 and fatty liver disease, ER stress or chronic inflammation to present research perspectives into the novel FGF21 functions in this broad and developing area of research.

Bottom Line: Various transcription factors induce FGF21 expression in the liver, which indicates that FGF21 is a mediator of multiple environmental cues.High serum levels of FGF21 are associated with NAFLD and its risk factors, such as endoplasmic reticulum stress and chronic inflammation.In this review, the research perspectives of FGF21 and therapeutic potencies of FGF21 as a modulator of NAFLD are summarized.

View Article: PubMed Central - PubMed

Affiliation: Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo , Tokyo , Japan.

ABSTRACT
Fibroblast growth factor 21 (FGF21) is a metabolic hormone primarily secreted from the liver and functions in multiple tissues. Various transcription factors induce FGF21 expression in the liver, which indicates that FGF21 is a mediator of multiple environmental cues. FGF21 alters metabolism under starvation conditions, protects the body from energy depletion, and extends life span. Pharmacological administration of FGF21 alleviates dyslipidemia and induces weight loss in obese animals. In addition to the well-studied functions of FG21, several lines of recent evidence indicate a possible link between FGF21 and non-alcoholic fatty liver disease (NAFLD). High serum levels of FGF21 are associated with NAFLD and its risk factors, such as endoplasmic reticulum stress and chronic inflammation. In addition, FGF21 alleviates the major risk factors of NAFLD, including obesity, dyslipidemia, and insulin insensitivity. Thus, FGF21 is a potential drug candidate for diseases, such as NAFLD, dyslipidemia, and type 2 diabetes. In this review, the research perspectives of FGF21 and therapeutic potencies of FGF21 as a modulator of NAFLD are summarized.

No MeSH data available.


Related in: MedlinePlus