期刊
CANCER LETTERS
卷 499, 期 -, 页码 5-13出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2020.11.026
关键词
Inflammation; Obesity; Oncogenic KRAS; Pancreatic cancer; Hepatocellular carcinoma
类别
资金
- National Institutes of Health [1R56DK123079-01, 1R01DK123079-01, 1R01CA240818]
- Start-up Fund from Stony Brook University
- Pilot Project Grant from the Department of Medicine at Stony Brook University
- National Key R&D Program of China [2017YFA0506000]
FGF21 is a novel metabolic regulator that acts as a stress sensor in tissues like the liver, promoting metabolic homeostasis through pathways that encourage lipid catabolism. Its signal pathway targets white and brown adipose tissues, playing a key role in preventing the development of diseases like fatty pancreas and steato-hepatitis.
The endocrine FGF21 was discovered as a novel metabolic regulator in 2005 with new functions bifurcating from the canonic heparin-binding FGFs that directly promote cell proliferation and growth independent of a co-receptor. Early studies have demonstrated that FGF21 is a stress sensor in the liver and possibly, several other endocrine and metabolic tissues. Hepatic FGF21 signals via endocrine routes to quench episodes of metabolic derangements, promoting metabolic homeostasis. The convergence of mouse and human studies shows that FGF21 promotes lipid catabolism, including lipolysis, fatty acid oxidation, mitochondrial oxidative activity, and thermogenic energy dissipation, rather than directly regulating insulin and appetite. The white and brown adipose tissues and, to some extent, the hypothalamus, all of which host a transmembrane receptor binary complex of FGFR1 and co-receptor KLB, are considered the essential tissue and molecular targets of hepatic or pharmacological FGF21. On the other hand, a growing body of work has revealed that pancreatic acinar cells form a constitutive high-production site for FGF21, which then acts in an autocrine or paracrine mode. Beyond regulation of macronutrient metabolism and physiological energy expenditure, FGF21 appears to function in forestalling the development of fatty pancreas, steato-pancreatitis, fatty liver, and steato-hepatitis, thereby preventing the development of advanced pathologies such as pancreatic ductal adenocarcinoma or hepatocellular carcinoma. This review is intended to provide updates on these new discoveries that illuminate the protective roles of FGF21-FGFR1-KLB signal pathway in metabolic anomalies-associated severe tissue damage and malignancy, and to inform potential new preventive or therapeutic strategies for obesity-inflicted cancer patients via reducing metabolic risks and inflammation.
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