Abstract
Non-alcoholic fatty liver disease (NAFLD) includes a cluster of liver disorders ranging
from simple fatty liver to non-alcoholic steatohepatitis (NASH) and cirrhosis. Due
to its liver and vascular complications, NAFLD has become a public health problem
with high morbidity and mortality. The pathogenesis of NAFLD is considered a “multi-hit
hypothesis” that involves lipotoxicity, oxidative stress, endoplasmic reticulum stress,
a chronic inflammatory state and mitochondrial dysfunction. Fibroblast growth factor
21 (FGF21) is a member of the fibroblast growth factor family with multiple metabolic
functions. FGF21 directly regulates lipid metabolism and reduces hepatic lipid accumulation
in an insulin-independent manner. Several studies have shown that FGF21 can ameliorate
the “multi-hits” in the pathogenesis of NAFLD. The administration of FGF21 reverses
hepatic steatosis, counteracts obesity and alleviates insulin resistance in rodents
and nonhuman primates. Using several strategies, we show that the reversal of simple
fatty liver and NASH is mediated by activation of the FGF21 signaling pathway. In
this review, we describe the molecular mechanisms involved in the onset and/or progression
of NAFLD, and review the current literature to highlight the therapeutic procedures
associated with the FGF21 signaling pathway for simple fatty liver and NASH, which
are the two most important types of NAFLD.
Abbreviations:
NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), FGF21 (fibroblast growth factor 21), SREBP-1c (sterol regulatory element-binding protein-1c), ACC (acetyl-CoA carboxylase), FAS (fatty acid synthase), SCD1 (stearoyl-CoA desaturase 1), ChREBP (carbohydrate response element binding protein), PKC (protein kinase C), ERK (extracellular regulated protein kinases), ROS (reactive oxygen species), IL-6 (interleukin-6), TNF-α (tumor necrosis factor-α), CRP (C-reactive protein), JNK (c-jun N-terminal kinase), IκB (inhibitor of nuclear factor-κB), NF-κB (nuclear factor-κB), CHOP (CCAAT enhancer binding protein homologous protein), FGFR (fibroblast growth factor receptor), PPARα (peroxisome proliferator activated receptor α), AMPK (AMP-activated protein kinase), SIRT1 (sirtuin 1), PPARγ (peroxisome proliferators-activated receptor γ), UCP-1 (uncoupling protein 1), UCP-2 (uncoupling protein 2), PI3K (phosphatidylinosistol 3-kinase), ATF4 (activating transcription factor 4), OLETF (Otsuka Long Evans Tokushima Fatty), GLP-1 (glucagon-like peptide-1), MCAD (medium-chain acyl-CoA dehydrogenase)Keywords
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References
- The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology.Gastroenterology. 2012; 142: 1592-1609
- Fibroblast growth factor 21: a novel metabolic regulator from pharmacology to physiology.Front Med. 2013; 7: 25-30
- Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice.Cell Metab. 2013; 17: 779-789
- Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice.Endocrinology. 2013; 154: 3099-3109
- FGF21 analogs of sustained action enabled by orthogonal biosynthesis demonstrate enhanced antidiabetic pharmacology in rodents.Diabetes. 2012; 61: 505-512
- Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice.Diabetes. 2009; 58: 250-259
- Fibroblast growth factor 21 corrects obesity in mice.Endocrinology. 2008; 149: 6018-6027
- The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21.Endocrinology. 2007; 148: 774-781
- Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice.Endocrinology. 2013; 154: 3366-3376
- Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH).Int J Mol Sci. 2013; 14: 20704-20728
- Pathology and biopsy assessment of non-alcoholic fatty liver disease.Dig Dis. 2010; 28: 197-202
- The link between fibroblast growth factor 21 and sterol regulatory element binding protein 1c during lipogenesis in hepatocytes.Mol Cell Endocrinol. 2011; 342: 41-47
- Chylomicron remnants and nonesterified fatty acids differ in their ability to inhibit genes involved in lipogenesis in rats.J Nutr. 2011; 141: 171-176
- Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease.J Gastroenterol. 2013; 48: 434-441
- A lipidomic analysis of nonalcoholic fatty liver disease.Hepatology. 2007; 46: 1081-1090
- The role of fatty acids in the development and progression of nonalcoholic fatty liver disease.J Nutr Biochem. 2008; 19: 567-576
- Non-alcoholic fatty liver disease and insulin resistance: from bench to bedside.Diabetes Metab. 2013; 39: 16-26
- Signalling mechanisms linking hepatic glucose and lipid metabolism.Diabetologia. 2006; 49: 1732-1741
- Association between insulin resistance and oxidative stress parameters in obese adolescents with non-alcoholic fatty liver disease.J Clin Res Pediatr Endocrinol. 2013; 5: 33-39
- Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance.J Endocrinol. 2013; 218: R25-R36
- Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance.World J Gastroenterol. 2010; 16: 4773-4783
- Cycloserine and threo-dihydrosphingosine inhibit TNF-alpha-induced cytotoxicity: evidence for the importance of de novo ceramide synthesis in TNF-alpha signaling.Biochim Biophys Acta. 2003; 1643: 1-4
- Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms.Mol Cell Biol. 2004; 24: 5434-5446
- PKC{delta} is activated in a dietary model of steatohepatitis and regulates endoplasmic reticulum stress and cell death.J Biol Chem. 2010; 285: 42115-42129
- Human leptin protein activates the growth of HepG2 cells by inhibiting PERK-mediated ER stress and apoptosis.Mol Med Rep. 2014; 10: 1649-1655
- The natural history of non-alcoholic fatty liver disease.Dig Dis. 2010; 28: 162-168
- The effects of fibroblast growth factor-21 knockdown and over-expression on its signaling pathway and glucose-lipid metabolism in vitro.Mol Cell Endocrinol. 2012; 348: 21-26
- Exendin-4 regulates lipid metabolism and fibroblast growth factor 21 in hepatic steatosis.Metabolism. 2014; 63: 1041-1048
- Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes.J Biol Chem. 2011; 286: 34559-34566
- PPARalpha is a key regulator of hepatic FGF21.Biochem Biophys Res Commun. 2007; 360: 437-440
- Circulating fibroblast growth factor 21 is induced by peroxisome proliferator-activated receptor agonists but not ketosis in man.J Clin Endocrinol Metab. 2009; 94: 3594-3601
- Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway.Proc Natl Acad Sci U S A. 2010; 107: 12553-12558
- Possible role of fibroblast growth factor 21 on atherosclerosis via amelioration of endoplasmic reticulum stress-mediated apoptosis in apoE mice.Heart Vessels. 2014; https://doi.org/10.1007/s00380-014-0557-9
- FGF21 promotes metabolic homeostasis via white adipose and leptin in mice.PLoS One. 2012; 7: e40164
- The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue.Mol Metab. 2012; 2: 31-37
- Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones.Cell. 2012; 148: 556-567
- Fibroblast growth factor-21 is expressed in neonatal and pheochromocytoma-induced adult human brown adipose tissue.Metabolism. 2014; 63: 312-317
- Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm in humans: relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis.J Clin Endocrinol Metab. 2013; 98: E98-E102
- Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin.Nat Med. 2011; 17: 55-63
- Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.J Clin Invest. 2006; 116: 1784-1792
- Mitochondrial dysfunction contributes to the increased vulnerabilities of adiponectin knockout mice to liver injury.Hepatology. 2008; 48: 1087-1096
- Fibroblast growth factor-21 protects human skeletal muscle myotubes from palmitate-induced insulin resistance by inhibiting stress kinase and NF-kappaB.Metabolism. 2012; 61: 1142-1151
- Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine.Am J Physiol Endocrinol Metab. 2014; 306: E469-E482
- FGF21 is an Akt-regulated myokine.FEBS Lett. 2008; 582: 3805-3810
- Intracellular signaling specificity in skeletal muscle in response to different modes of exercise.J Appl Physiol (1985). 2001; 90: 1936-1942
- Fibroblast growth factor 21: a promising therapeutic target in obesity-related diseases.Expert Rev Cardiovasc Ther. 2014; 12: 659-666
- Fibroblast growth factor-21 is induced in human skeletal muscles by hyperinsulinemia.Diabetes. 2009; 58: 2797-2801
- Decrease in circulating fibroblast growth factor 21 after an oral fat load is related to postprandial triglyceride-rich lipoproteins and liver fat.Eur J Endocrinol. 2012; 166: 487-492
- Metabolically protective cytokines adiponectin and fibroblast growth factor-21 are increased by acute overfeeding in healthy humans.PLoS One. 2013; 8: e78864
- Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21.Diabetes. 2009; 58: 1532-1538
- Cobalt chloride decreases fibroblast growth factor-21 expression dependent on oxidative stress but not hypoxia-inducible factor in Caco-2 cells.Toxicol Appl Pharmacol. 2012; 264: 212-221
- Fibroblast growth factor 21 is induced by endoplasmic reticulum stress.Biochimie. 2013; 95: 692-699
- ATF4- and CHOP-dependent induction of FGF21 through endoplasmic reticulum stress.Biomed Res Int. 2014; 2014: 807874
- Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance.Diabetes Care. 2009; 32: 1542-1546
- Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease.Cardiovasc Diabetol. 2013; 12: 124
- Identification of a support vector machine-based biomarker panel with high sensitivity and specificity for nonalcoholic steatohepatitis.Clin Chim Acta. 2012; 414: 154-157
- Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers.J Hepatol. 2012; 56: 1363-1370
- Circulating fibroblast growth factor 21 levels are closely associated with hepatic fat content: a cross-sectional study.PLoS One. 2011; 6: e24895
- Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis.Eur J Gastroenterol Hepatol. 2011; 23: 382-388
- Serum FGF21 levels are increased in newly diagnosed type 2 diabetes with nonalcoholic fatty liver disease and associated with hsCRP levels independently.Diabetes Res Clin Pract. 2011; 93: 10-16
- Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease.Eur J Clin Invest. 2010; 40: 887-892
- Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride.J Hepatol. 2010; 53: 934-940
- Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease.Gastroenterology. 2010; 139: 456-463
- High serum level of fibroblast growth factor 21 is an independent predictor of non-alcoholic fatty liver disease: a 3-year prospective study in China.J Hepatol. 2013; 58: 557-563
- Liraglutide increases FGF-21 activity and insulin sensitivity in high fat diet and adiponectin knockdown induced insulin resistance.PLoS One. 2012; 7: e48392
- Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial.Diabetologia. 2011; 54: 3093-3100
- Obesity is a fibroblast growth factor 21 (FGF21)-resistant state.Diabetes. 2010; 59: 2781-2789
- TNF-alpha represses beta-Klotho expression and impairs FGF21 action in adipose cells: involvement of JNK1 in the FGF21 pathway.Endocrinology. 2012; 153: 4238-4245
- Modulating fibroblast growth factor 21 in hyperphagic OLETF rats with daily exercise and caloric restriction.Appl Physiol Nutr Metab. 2012; 37: 1054-1062
- High glucose represses beta-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets: involvement of peroxisome proliferator-activated receptor gamma signaling.Diabetes. 2013; 62: 3751-3759
- Fibroblast growth factor 21 (FGF-21) and its relation to obesity, metabolic syndrome, and nonalcoholic fatty liver in children: a longitudinal analysis.J Clin Endocrinol Metab. 2012; 97: 2143-2150
- Effects of short-term continuous subcutaneous insulin infusion on fasting plasma fibroblast growth factor-21 levels in patients with newly diagnosed type 2 diabetes mellitus.PLoS One. 2011; 6: e26359
- Relation between fibroblast growth factor-21, adiposity, metabolism, and weight reduction.Metabolism. 2011; 60: 306-311
- Effects of rosiglitazone on fasting plasma fibroblast growth factor-21 levels in patients with type 2 diabetes mellitus.Eur J Endocrinol. 2009; 161: 391-395
- Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity.Clin Endocrinol (Oxf). 2009; 71: 369-375
- The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man.Cell Metab. 2008; 8: 169-174
- Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21.Gastroenterology. 2014; 146: 539-49 e7
- Hypocaloric high-protein diet improves fatty liver and hypertriglyceridemia in sucrose-fed obese rats via two pathways.Am J Physiol Endocrinol Metab. 2009; 297: E76-E84
- Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice.Obesity (Silver Spring). 2011; 19: 1396-1403
- Artemisia scoparia extract attenuates non-alcoholic fatty liver disease in diet-induced obesity mice by enhancing hepatic insulin and AMPK signaling independently of FGF21 pathway.Metabolism. 2013; 62: 1239-1249
- Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes.Diabetes. 2005; 54: 603-608
- Exercise increases serum fibroblast growth factor 21 (FGF21) levels.PLoS One. 2012; 7: e38022
- Effects of fenofibrate and xuezhikang on high-fat diet-induced non-alcoholic fatty liver disease.Clin Exp Pharmacol Physiol. 2007; 34: 27-35
- Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates.J Hepatol. 2006; 44: 732-741
- Effect of metformin on ballooning degeneration in nonalcoholic steatohepatitis (NASH): when to use metformin in nonalcoholic fatty liver disease (NAFLD).Adv Ther. 2014; 31: 30-43
- Metformin stimulates FGF21 expression in primary hepatocytes.Exp Diabetes Res. 2012; 2012: 465282
- The role of metformin in the management of NAFLD.Exp Diabetes Res. 2012; 2012: 716404
- Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans.Diabetes. 2008; 57: 1246-1253
- Pharmacokinetics, safety, and efficacy of DPP-4 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus and renal or hepatic impairment. A systematic review of the literature.Endocrine. 2014; https://doi.org/10.1007/s12020-014-0179-0
- Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice.Am J Physiol Gastrointest Liver Physiol. 2012; 302: G762-G772
- Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists.PLoS One. 2012; 7: e50117
- Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years.Curr Med Res Opin. 2008; 24: 275-286
- Effects of sitagliptin in diabetic patients with nonalcoholic steatohepatitis.Acta Gastroenterol Belg. 2012; 75: 240-244
- Gene therapy for diabetes: metabolic effects of helper-dependent adenoviral exendin 4 expression in a diet-induced obesity mouse model.Mol Ther. 2008; 16: 1805-1812
- Effects of resveratrol in experimental and clinical non-alcoholic fatty liver disease.World J Hepatol. 2014; 6: 188-198
- Differential effects of low-dose resveratrol on adiposity and hepatic steatosis in diet-induced obese mice.Br J Nutr. 2012; 108: 2166-2175
- Rational design of a fibroblast growth factor 21-based clinical candidate, LY2405319.PLoS One. 2013; 8: e58575
Article info
Publication history
Published online: November 27, 2014
Accepted:
November 25,
2014
Received:
June 30,
2014
Footnotes
☆Disclosure statement: The authors have nothing to disclose.
Identification
Copyright
© 2015 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
