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Publication
Journal: Journal of Pathology
March/20/2008
Abstract
Fibrosis is defined by the over<em>growth</em>, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myo<em>fibroblast</em>, which when activated serves as the primary collagen-producing cell. Myo<em>fibroblasts</em> are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating <em>fibroblast</em>-like cells called fibrocytes that are derived from bone-marrow stem cells. Myo<em>fibroblasts</em> are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine <em>factors</em> secreted by myo<em>fibroblasts</em>, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on <em>fibroblasts</em>. Cytokines (IL-13, IL-<em>21</em>, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic <em>factors</em> (VEGF), <em>growth</em> <em>factors</em> (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.
Authors
Publication
Journal: Nature
January/12/2009
Abstract
MicroRNAs comprise a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs. Dysregulation of microRNAs by several mechanisms has been described in various disease states including cardiac disease. Whereas previous studies of cardiac disease have focused on microRNAs that are primarily expressed in cardiomyocytes, the role of microRNAs expressed in other cell types of the heart is unclear. Here we show that microRNA-<em>21</em> (miR-<em>21</em>, also known as Mirn<em>21</em>) regulates the ERK-MAP kinase signalling pathway in cardiac <em>fibroblasts</em>, which has impacts on global cardiac structure and function. miR-<em>21</em> levels are increased selectively in <em>fibroblasts</em> of the failing heart, augmenting ERK-MAP kinase activity through inhibition of sprouty homologue 1 (Spry1). This mechanism regulates <em>fibroblast</em> survival and <em>growth</em> <em>factor</em> secretion, apparently controlling the extent of interstitial fibrosis and cardiac hypertrophy. In vivo silencing of miR-<em>21</em> by a specific antagomir in a mouse pressure-overload-induced disease model reduces cardiac ERK-MAP kinase activity, inhibits interstitial fibrosis and attenuates cardiac dysfunction. These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac <em>fibroblasts</em>. Our results validate miR-<em>21</em> as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.
Publication
Journal: Cell Metabolism
July/2/2008
Abstract
Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the utilization of fat as an energy source during starvation and is the molecular target for the fibrate dyslipidemia drugs. Here, we identify the endocrine hormone <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) as a mediator of the pleiotropic actions of PPARalpha. FGF<em>21</em> is induced directly by PPARalpha in liver in response to fasting and PPARalpha agonists. FGF<em>21</em> in turn stimulates lipolysis in white adipose tissue and ketogenesis in liver. FGF<em>21</em> also reduces physical activity and promotes torpor, a short-term hibernation-like state of regulated hypothermia that conserves energy. These findings demonstrate an unexpected role for the PPARalpha-FGF<em>21</em> endocrine signaling pathway in regulating diverse metabolic and behavioral aspects of the adaptive response to starvation.
Publication
Journal: Cell Metabolism
July/2/2008
Abstract
Mice fed a high-fat, low-carbohydrate ketogenic diet (KD) exhibit marked changes in hepatic metabolism and energy homeostasis. Here, we identify liver-derived <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) as an endocrine regulator of the ketotic state. Hepatic expression and circulating levels of FGF<em>21</em> are induced by both KD and fasting, are rapidly suppressed by refeeding, and are in large part downstream of PPARalpha. Importantly, adenoviral knockdown of hepatic FGF<em>21</em> in KD-fed mice causes fatty liver, lipemia, and reduced serum ketones, due at least in part to altered expression of key genes governing lipid and ketone metabolism. Hence, induction of FGF<em>21</em> in liver is required for the normal activation of hepatic lipid oxidation, triglyceride clearance, and ketogenesis induced by KD. These findings identify hepatic FGF<em>21</em> as a critical regulator of lipid homeostasis and identify a physiological role for this hepatic hormone.
Publication
Journal: Nature Genetics
January/19/2015
Abstract
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼<em>21</em>%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in <em>growth</em> and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by <em>fibroblast</em> <em>growth</em> <em>factors</em>, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal <em>growth</em>, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Publication
Journal: Genes and Development
March/11/2012
Abstract
Certain white adipose tissue (WAT) depots are readily able to convert to a "brown-like" state with prolonged cold exposure or exposure to β-adrenergic compounds. This process is characterized by the appearance of pockets of uncoupling protein 1 (UCP1)-positive, multilocular adipocytes and serves to increase the thermogenic capacity of the organism. We show here that <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) plays a physiologic role in this thermogenic recruitment of WATs. In fact, mice deficient in FGF<em>21</em> display an impaired ability to adapt to chronic cold exposure, with diminished browning of WAT. Adipose-derived FGF<em>21</em> acts in an autocrine/paracrine manner to increase expression of UCP1 and other thermogenic genes in fat tissues. FGF<em>21</em> regulates this process, at least in part, by enhancing adipose tissue PGC-1α protein levels independently of mRNA expression. We conclude that FGF<em>21</em> acts to activate and expand the thermogenic machinery in vivo to provide a robust defense against hypothermia.
Publication
Journal: Biochemical and Biophysical Research Communications
July/23/1989
Abstract
A <em>growth</em> <em>factor</em> for vascular endothelial cells was identified in the media conditioned by bovine pituitary follicular cells and purified to homogeneity by a combination of ammonium sulfate precipitation, heparin-sepharose affinity chromatography and two reversed phase HPLC steps. The <em>growth</em> <em>factor</em> was a cationic, heat stable and relatively acid stable protein and had a molecular weight, as assessed by silver-stained SDS-PAGE gel, of approximately 45,000 under non reducing conditions and approximately 23,000 under reducing conditions. The purified <em>growth</em> <em>factor</em> had a maximal mitogenic effect on adrenal cortex-derived capillary endothelial cells at the concentration of 1-1.2 ng/ml (22-26 pM). Further characterization of the bioactivity of the <em>growth</em> <em>factor</em> reveals that it exerts mitogenic effects also on vascular endothelial cells isolated from several districts but not on adrenal cortex cells, lens epithelial cells, corneal endothelial cells, keratynocytes or BHK-<em>21</em> <em>fibroblasts</em>, indicating that its target cells specificity is unlike that of any previously characterized <em>growth</em> <em>factor</em>. Microsequencing reveals a unique N-terminal amino acid sequence. On the basis of its apparent target cell selectivity, we propose to name this <em>factor</em> vascular endothelial <em>growth</em> <em>factor</em> (VEGF).
Publication
Journal: Diabetes
March/29/2009
Abstract
OBJECTIVE
<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF<em>21</em> in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet-induced obesity (DIO) model.
METHODS
DIO or normal lean mice were treated with vehicle or recombinant murine FGF<em>21</em>. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques.
RESULTS
FGF<em>21</em> dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF<em>21</em> also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF<em>21</em> inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF<em>21</em> also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity.
CONCLUSIONS
FGF<em>21</em> corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic steatosis, obesity, and type 2 diabetes.
Publication
Journal: Endocrinology
March/30/2009
Abstract
<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) is a metabolic regulator that provides efficient and durable glycemic and lipid control in various animal models. However, its potential to treat obesity, a major health concern affecting over 30% of the population, has not been fully explored. Here we report that systemic administration of FGF<em>21</em> for 2 wk in diet-induced obese and ob/ob mice lowered their mean body weight by 20% predominantly via a reduction in adiposity. Although no decrease in total caloric intake or effect on physical activity was observed, FGF<em>21</em>-treated animals exhibited increased energy expenditure, fat utilization, and lipid excretion, reduced hepatosteatosis, and ameliorated glycemia. Transcriptional and blood cytokine profiling studies revealed effects consistent with the ability of FGF<em>21</em> to ameliorate insulin and leptin resistance, enhance fat oxidation and suppress de novo lipogenesis in liver as well as to activate futile cycling in adipose. Overall, these data suggest that FGF<em>21</em> exhibits the therapeutic characteristics necessary for an effective treatment of obesity and fatty liver disease and provides novel insights into the metabolic determinants of these activities.
Publication
Journal: Diabetes
August/3/2008
Abstract
OBJECTIVE
<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) is a metabolic regulator with multiple beneficial effects on glucose homeostasis and insulin sensitivity in animal models. This study aimed to investigate the relationship between its serum levels and various cardiometabolic parameters in humans.
METHODS
A newly developed immunoassay was used to measure serum FGF<em>21</em> levels in 232 Chinese subjects recruited from our previous cross-sectional studies. The mRNA expression levels of FGF<em>21</em> in the liver and adipose tissues were quantified by real-time PCR.
RESULTS
Serum FGF<em>21</em> levels in overweight/obese subjects were significantly higher than in lean individuals. Serum FGF<em>21</em> correlated positively with adiposity, fasting insulin, and triglycerides but negatively with HDL cholesterol, after adjusting for age and BMI. Logistic regression analysis demonstrated an independent association between serum FGF<em>21</em> and the metabolic syndrome. Furthermore, the increased risk of the metabolic syndrome associated with high serum FGF<em>21</em> was over and above the effects of individual components of the metabolic syndrome. Our in vitro study detected a differentiation-dependent expression of FGF<em>21</em> in 3T3-L1 adipocytes and human adipocytes. In db/db obese mice, FGF<em>21</em> mRNA expression was markedly increased in both the liver and adipose tissue compared with that in their lean littermates. Furthermore, FGF<em>21</em> expression in subcutaneous fat correlated well with its circulating concentrations in humans.
CONCLUSIONS
FGF<em>21</em> is a novel adipokine associated with obesity-related metabolic complications in humans. The paradoxical increase of serum FGF<em>21</em> in obese individuals, which may be explained by a compensatory response or resistance to FGF<em>21</em>, warrants further investigation.
Publication
Journal: New England Journal of Medicine
April/28/2003
Abstract
BACKGROUND
Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it.
METHODS
Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied.
RESULTS
Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia.
CONCLUSIONS
FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. FGF-23 measurements might improve the management of phosphate-wasting disorders.