Citations
All
Search in:AllTitleAbstractAuthor name
Publications
(3K+)
Patents
Grants
Pathways
Clinical trials
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.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
September/27/2009
Abstract
The liver plays a crucial role in mobilizing energy during nutritional deprivation. During the early stages of fasting, hepatic glycogenolysis is a primary energy source. As fasting progresses and glycogen stores are depleted, hepatic gluconeogenesis and ketogenesis become major energy sources. Here, we show that <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>), a hormone that is induced in liver by fasting, induces hepatic expression of peroxisome proliferator-activated receptor gamma coactivator protein-1alpha (PGC-1alpha), a key transcriptional regulator of energy homeostasis, and causes corresponding increases in fatty acid oxidation, tricarboxylic acid cycle flux, and gluconeogenesis without increasing glycogenolysis. Mice lacking FGF<em>21</em> fail to fully induce PGC-1alpha expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis. These results reveal an unexpected relationship between FGF<em>21</em> and PGC-1alpha and demonstrate an important role for FGF<em>21</em> in coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation.
Publication
Journal: Nature Medicine
March/5/2013
Abstract
Despite <em>growing</em> interest and a recent surge in papers, the role of autophagy in glucose and lipid metabolism is unclear. We produced mice with skeletal muscle-specific deletion of Atg7 (encoding autophagy-related 7). Unexpectedly, these mice showed decreased fat mass and were protected from diet-induced obesity and insulin resistance; this phenotype was accompanied by increased fatty acid oxidation and browning of white adipose tissue (WAT) owing to induction of <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (Fgf<em>21</em>). Mitochondrial dysfunction induced by autophagy deficiency increased Fgf<em>21</em> expression through induction of Atf4, a master regulator of the integrated stress response. Mitochondrial respiratory chain inhibitors also induced Fgf<em>21</em> in an Atf4-dependent manner. We also observed induction of Fgf<em>21</em>, resistance to diet-induced obesity and amelioration of insulin resistance in mice with autophagy deficiency in the liver, another insulin target tissue. These findings suggest that autophagy deficiency and subsequent mitochondrial dysfunction promote Fgf<em>21</em> expression, a hormone we consequently term a 'mitokine', and together these processes promote protection from diet-induced obesity and insulin resistance.
Publication
Journal: Endocrinology
February/26/2007
Abstract
<em>Fibroblast</em> <em>growth</em> <em>factor</em> (FGF)-<em>21</em> has been recently characterized as a potent metabolic regulator. Systemic administration of FGF-<em>21</em> reduced plasma glucose and triglycerides to near normal levels in genetically compromised diabetic rodents. Importantly, these effects were durable and did not come at the expense of weight gain, hypoglycemia, or mitogenicity. To explore the therapeutic properties of FGF-<em>21</em> in a nongenetically modified primate species, and thus demonstrate the potential for efficacy in humans, we evaluated its bioactivity in diabetic nonhuman primates. When administered daily for 6 wk to diabetic rhesus monkeys, FGF-<em>21</em> caused a dramatic decline in fasting plasma glucose, fructosamine, triglycerides, insulin, and glucagon. Of significant importance in regard to safety, hypoglycemia was not observed at any point during the study. FGF-<em>21</em> administration also led to significant improvements in lipoprotein profiles, including lowering of low-density lipoprotein cholesterol and raising of high-density lipoprotein cholesterol, beneficial changes in the circulating levels of several cardiovascular risk markers/<em>factors</em>, and the induction of a small but significant weight loss. These data support the development of FGF-<em>21</em> for the treatment of diabetes and other metabolic diseases.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
December/15/1998
Abstract
Human pluripotent stem cells would be invaluable for in vitro studies of aspects of human embryogenesis. With the goal of establishing pluripotent stem cell lines, gonadal ridges and mesenteries containing primordial germ cells (PGCs, 5-9 weeks postfertilization) were cultured on mouse STO <em>fibroblast</em> feeder layers in the presence of human recombinant leukemia inhibitory <em>factor</em>, human recombinant basic <em>fibroblast</em> <em>growth</em> <em>factor</em>, and forskolin. Initially, single PGCs in culture were visualized by alkaline phosphatase activity staining. Over a period of 7-<em>21</em> days, PGCs gave rise to large multicellular colonies resembling those of mouse pluripotent stem cells termed embryonic stem and embryonic germ (EG) cells. Throughout the culture period most cells within the colonies continued to be alkaline phosphatase-positive and tested positive against a panel of five immunological markers (SSEA-1, SSEA-3, SSEA-4, TRA-1-60, and TRA-1-81) that have been used routinely to characterize embryonic stem and EG cells. The cultured cells have been continuously passaged and found to be karyotypically normal and stable. Both XX and XY cell cultures have been obtained. Immunohistochemical analysis of embryoid bodies collected from these cultures revealed a wide variety of differentiated cell types, including derivatives of all three embryonic germ layers. Based on their origin and demonstrated properties, these human PGC-derived cultures meet the criteria for pluripotent stem cells and most closely resemble EG cells.
Publication
Journal: Diabetes
November/15/2010
Abstract
OBJECTIVE
<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF<em>21</em> improve glucose tolerance, lower serum free fatty acids, and lead to weight loss in obese mice. Surprisingly, however, FGF<em>21</em> levels are elevated in obese ob/ob and db/db mice and correlate positively with BMI in humans. However, the expected beneficial effects of endogenous FGF<em>21</em> to increase glucose tolerance and reduce circulating triglycerides are absent in obesity.
METHODS
To test the hypothesis that obesity is a state of FGF<em>21</em> resistance, we evaluated the response of obese mice to exogenous FGF<em>21</em> administration. In doing this, we assessed the impact of diet-induced obesity on FGF<em>21</em> signaling and resultant transcriptional events in the liver and white adipose tissue. We also analyzed the physiologic impact of FGF<em>21</em> resistance by assessing serum parameters that are acutely regulated by FGF<em>21</em>.
RESULTS
When obese mice are treated with FGF<em>21</em>, they display both a significantly attenuated signaling response as assessed by extracellular mitogen-activated protein kinase 1 and 2 (ERK1/2) phosphorylation as well as an impaired induction of FGF<em>21</em> target genes, including cFos and EGR1. These effects were seen in both liver and fat. Similarly, changes in serum parameters such as the decline in glucose and free fatty acids are attenuated in FGF<em>21</em>-treated DIO mice.
CONCLUSIONS
These data demonstrate that DIO mice have increased endogenous levels of FGF<em>21</em> and respond poorly to exogenous FGF<em>21</em>. We therefore propose that obesity is an FGF<em>21</em>-resistant state.
Publication
Journal: Cell Metabolism
March/20/2014
Abstract
<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) is a recently discovered metabolic regulator. Exogenous FGF<em>21</em> produces beneficial metabolic effects in animal models; however, the translation of these observations to humans has not been tested. Here, we studied the effects of LY2405319 (LY), a variant of FGF<em>21</em>, in a randomized, placebo-controlled, double-blind proof-of-concept trial in patients with obesity and type 2 diabetes. Patients received placebo or 3, 10, or 20 mg of LY daily for 28 days. LY treatment produced significant improvements in dyslipidemia, including decreases in low-density lipoprotein cholesterol and triglycerides and increases in high-density lipoprotein cholesterol and a shift to a potentially less atherogenic apolipoprotein concentration profile. Favorable effects on body weight, fasting insulin, and adiponectin were also detected. However, only a trend toward glucose lowering was observed. These results indicate that FGF<em>21</em> is bioactive in humans and suggest that FGF<em>21</em>-based therapies may be effective for the treatment of selected metabolic disorders.
Publication
Journal: Gastroenterology
November/11/2013
Abstract
OBJECTIVE
Obeticholic acid (OCA; INT-747, 6α-ethyl-chenodeoxycholic acid) is a semisynthetic derivative of the primary human bile acid chenodeoxycholic acid, the natural agonist of the farnesoid X receptor, which is a nuclear hormone receptor that regulates glucose and lipid metabolism. In animal models, OCA decreases insulin resistance and hepatic steatosis.
METHODS
We performed a double-blind, placebo-controlled, proof-of-concept study to evaluate the effects of OCA on insulin sensitivity in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Patients were randomly assigned to groups given placebo (n = 23), 25 mg OCA (n = 20), or 50 mg OCA (n = <em>21</em>) once daily for 6 weeks. A 2-stage hyperinsulinemic-euglycemic insulin clamp was used to measure insulin sensitivity before and after the 6-week treatment period. We also measured levels of liver enzymes, lipid analytes, <em>fibroblast</em> <em>growth</em> <em>factor</em> 19, 7α-hydroxy-4-cholesten-3-one (a BA precursor), endogenous bile acids, and markers of liver fibrosis.
RESULTS
When patients were given a low-dose insulin infusion, insulin sensitivity increased by 28.0% from baseline in the group treated with 25 mg OCA (P = .019) and 20.1% from baseline in the group treated with 50 mg OCA (P = .060). Insulin sensitivity increased by 24.5% (P = .011) in combined OCA groups, whereas it decreased by 5.5% in the placebo group. A similar pattern was observed in patients given a high-dose insulin infusion. The OCA groups had significant reductions in levels of γ-glutamyltransferase and alanine aminotransferase and dose-related weight loss. They also had increased serum levels of low-density lipoprotein cholesterol and fibroblast growth factor 19, associated with decreased levels of 7α-hydroxy-4-cholesten-3-one and endogenous bile acids, indicating activation of farnesoid X receptor. Markers of liver fibrosis decreased significantly in the group treated with 25 mg OCA. Adverse experiences were similar among groups.
CONCLUSIONS
In this phase 2 trial, administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Longer and larger studies are warranted. ClinicalTrials.gov, Number: NCT00501592.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
June/19/2007
Abstract
<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) is a liver-derived endocrine <em>factor</em> that stimulates glucose uptake in adipocytes. Here, we show that FGF<em>21</em> activity depends on betaKlotho, a single-pass transmembrane protein whose expression is induced during differentiation from preadipocytes to adipocytes. BetaKlotho physically interacts with FGF receptors 1c and 4, thereby increasing the ability of these FGF receptors to bind FGF<em>21</em> and activate the MAP kinase cascade. Knockdown of betaKlotho expression by siRNA in adipocytes diminishes glucose uptake induced by FGF<em>21</em>. Importantly, administration of FGF<em>21</em> into mice induces MAP kinase phosphorylation in white adipose tissue and not in tissues without betaKlotho expression. Thus, betaKlotho functions as a co<em>factor</em> essential for FGF<em>21</em> activity.
Publication
Journal: Cell
March/18/2012
Abstract
<em>Fibroblast</em> <em>growth</em> <em>factor</em>-<em>21</em> (FGF<em>21</em>) is a circulating hepatokine that beneficially affects carbohydrate and lipid metabolism. Here, we report that FGF<em>21</em> is also an inducible, fed-state autocrine <em>factor</em> in adipose tissue that functions in a feed-forward loop to regulate the activity of peroxisome proliferator-activated receptor γ (PPARγ), a master transcriptional regulator of adipogenesis. FGF<em>21</em> knockout (KO) mice display defects in PPARγ signaling including decreased body fat and attenuation of PPARγ-dependent gene expression. Moreover, FGF<em>21</em>-KO mice are refractory to both the beneficial insulin-sensitizing effects and the detrimental weight gain and edema side effects of the PPARγ agonist rosiglitazone. This loss of function in FGF<em>21</em>-KO mice is coincident with a marked increase in the sumoylation of PPARγ, which reduces its transcriptional activity. Adding back FGF<em>21</em> prevents sumoylation and restores PPARγ activity. Collectively, these results reveal FGF<em>21</em> as a key mediator of the physiologic and pharmacologic actions of PPARγ.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
April/24/2002
Abstract
One approach to resolving the complexities of chondrogenesis is to examine simplified systems in vitro. We analyzed cartilage differentiation by human adult stem cells from bone marrow stroma. Marrow stromal cells were cultured as micromass pellets for <em>21</em> days in serum-free medium containing transforming <em>growth</em> <em>factor</em> (TGF)-beta3, dexamethasone, and bone morphogenetic protein (BMP)-6. Assays for pulse-labeled [3H]DNA and for total DNA indicated that there was little proliferation and a progressive loss of cells in the pellets. There were continuous increases in mRNAs for cartilage matrix (proteoglycans and COL2, -9, -10, and -11), receptors [<em>fibroblast</em> <em>growth</em> <em>factor</em> 2 (FGFR2) and parathyroid hormone-related peptide receptor (PTHrP-R)], and transcription <em>factors</em> (SOX5, -6, and -9) as demonstrated by histochemical and microarray assays. Reverse transcription-PCR assays for 11 mRNAs confirmed the microarray data. SOX4, vascular endothelial <em>growth</em> <em>factor</em> (VEGF), and matrix metalloproteinase 14 (MMP14) increased at day 1 and decreased thereafter, suggesting roles early in chondrogenesis. Also, forkhead, CD10, and MMP13 increased up to day 7 and decreased thereafter, suggesting roles in an intermediate stage of chondrogenesis. In addition, two collagens (COL3A1 and COL16A1), a signaling molecule (WNT11), a homeobox homolog (BAPX1), a receptor (IL-1R1), an IGFs modulator (IGFBP5), and a mettaloproteinase (MMP16) increased progressively up to about day 14, suggesting roles later in chondrogenesis. Our results indicate that the simplicity of the system makes it possible to define in detail the cellular and molecular events during chondrogenesis.
Publication
Journal: Molecular and Cellular Biology
May/31/2007
Abstract
Unique among <em>fibroblast</em> <em>growth</em> <em>factors</em> (FGFs), FGF19, -<em>21</em>, and -23 act in an endocrine fashion to regulate energy, bile acid, glucose, lipid, phosphate, and vitamin D homeostasis. These FGFs require the presence of Klotho/betaKlotho in their target tissues. Here, we present the crystal structures of FGF19 alone and FGF23 in complex with sucrose octasulfate, a disaccharide chemically related to heparin. The conformation of the heparin-binding region between beta strands 10 and 12 in FGF19 and FGF23 diverges completely from the common conformation adopted by paracrine-acting FGFs. A cleft between this region and the beta1-beta2 loop, the other heparin-binding region, precludes direct interaction between heparin/heparan sulfate and backbone atoms of FGF19/23. This reduces the heparin-binding affinity of these ligands and confers endocrine function. Klotho/betaKlotho have evolved as a compensatory mechanism for the poor ability of heparin/heparan sulfate to promote binding of FGF19, -<em>21</em>, and -23 to their cognate receptors.
Publication
Journal: Cell Metabolism
March/30/2014
Abstract
<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) is a metabolic hormone with pleiotropic effects on regulating glucose and lipid homeostasis and insulin sensitivity. However, the mechanisms underlying the metabolic actions of FGF<em>21</em> remain unknown. Here we show that the insulin-sensitizing adipokine adiponectin is a downstream effector of FGF<em>21</em>. Treatments with FGF<em>21</em> enhanced both expression and secretion of adiponectin in adipocytes, thereby increasing serum levels of adiponectin in mice. Adiponectin knockout mice were refractory to several therapeutic benefits of FGF<em>21</em>, including alleviation of obesity-associated hyperglycemia, hypertriglyceridemia, insulin resistance, and hepatic steatosis. Furthermore, the effects of FGF<em>21</em> on attenuation of obesity-induced impairment in insulin signaling in liver and skeletal muscle were abrogated in adiponectin knockout mice, whereas FGF<em>21</em>-mediated activation of ERK1/ERK2 in adipose tissues remained unaffected. Therefore, adiponectin couples FGF<em>21</em> actions in local adipocytes to liver and skeletal muscle, thereby mediating the systemic effects of FGF<em>21</em> on energy metabolism and insulin sensitivity.
Publication
Journal: Gastroenterology
August/11/2010
Abstract
OBJECTIVE
<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) is an hepatic protein that plays a critical role in metabolism, stimulating fatty acid oxidation in liver and glucose uptake in fat. Systemic administration to obese rodents and diabetic monkeys leads to improved glucose homeostasis and weight loss. In rodents, FGF<em>21</em> increases with fasting and consumption of a ketogenic diet (KD). In humans, FGF<em>21</em> correlates with body mass index (BMI), but studies evaluating other parameters show inconsistent results. We examined FGF<em>21</em> serum levels in lean and obese individuals and in response to dietary manipulation. We also evaluated FGF<em>21</em> serum levels and liver messenger RNA (mRNA) expression in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
METHODS
Serum FGF<em>21</em> was measured after an overnight fast in individuals with BMI ranging from normal to obese. Volunteers fasted for 16 or 72 hours and then ate a standard meal. Another group consumed KD for 12 days. Serum FGF<em>21</em> and hepatic mRNA expression were measured in obese individuals with NAFLD or NASH.
RESULTS
There was a positive correlation between BMI and FGF<em>21</em>. There was no change in FGF<em>21</em> in response to a short fast or KD. A nonstatistically significant fall in FGF<em>21</em> levels was seen after a 72-hour fast. Hepatic FGF<em>21</em> mRNA expression was significantly elevated in NAFLD, which correlated with a substantial increase in serum FGF<em>21</em>. In NASH, serum FGF<em>21</em> but not liver mRNA was increased.
CONCLUSIONS
FGF<em>21</em> correlates with BMI and may be a novel biomarker for NAFLD, but is not nutritionally regulated in humans.
load more...