The liver and intestine play crucial roles in maintaining bile acid homeostasis. Here, we demonstrate that fibroblast growth factor 15 (FGF15) signals from intestine to liver to repress the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1), which catalyzes the first and rate-limiting step in the classical bile acid synthetic pathway. FGF15 expression is stimulated in the small intestine by the nuclear bile acid receptor FXR and represses Cyp7a1 in liver through a mechanism that involves FGF receptor 4 (FGFR4) and the orphan nuclear receptor SHP. Mice lacking FGF15 have increased hepatic CYP7A1 mRNA and protein levels and corresponding increases in CYP7A1 enzyme activity and fecal bile acid excretion. These studies define FGF15 and FGFR4 as components of a gut-liver signaling pathway that synergizes with SHP to regulate bile acid synthesis.

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 fibroblast growth factor 21 (FGF21) as a mediator of the pleiotropic actions of PPARalpha. FGF21 is induced directly by PPARalpha in liver in response to fasting and PPARalpha agonists. FGF21 in turn stimulates lipolysis in white adipose tissue and ketogenesis in liver. FGF21 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-FGF21 endocrine signaling pathway in regulating diverse metabolic and behavioral aspects of the adaptive response to starvation.

Diverse forms of injury and stress evoke a hypertrophic growth response in adult cardiac myocytes, which is characterized by an increase in cell size, enhanced protein synthesis, assembly of sarcomeres, and reactivation of fetal genes, often culminating in heart failure and sudden death. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs that were regulated during cardiac hypertrophy and heart failure. We describe >12 miRNAs that are up-or down-regulated in cardiac tissue from mice in response to transverse aortic constriction or expression of activated calcineurin, stimuli that induce pathological cardiac remodeling. Many of these miRNAs were similarly regulated in failing human hearts. Forced overexpression of stress-inducible miRNAs was sufficient to induce hypertrophy in cultured cardiomyocytes. Similarly, cardiac overexpression of miR-195, which was up-regulated during cardiac hypertrophy, resulted in pathological cardiac growth and heart failure in transgenic mice. These findings reveal an important role for specific miRNAs in the control of hypertrophic growth and chamber remodeling of the heart in response to pathological signaling and point to miRNAs as potential therapeutic targets in heart disease.calcineurin ͉ myosin heavy chain ͉ thoracic aortic banding ͉ cardiomyocytes

We employed homologous recombination in embryonic stem cells to produce mice lacking functional LDL receptor genes. Homozygous male and female mice lacking LDL receptors (LDLR-'-mice) were viable and fertile. Total plasma cholesterol levels were twofold higher than those of wild-type littermates, owing to a seven-to ninefold increase in intermediate density lipoproteins (IDL) and LDL without a significant change in HDL. Plasma triglyceride levels were normal. The half-lives for intravenously administered 1251-VLDL and 1251_ LDL were prolonged by 30-fold and 2.5-fold, respectively, but the clearance of '251-HDL was normal in the LDLR-'-mice. Unlike wild-type mice, LDLR-1-mice responded to moderate amounts of dietary cholesterol (0.2% cholesterol/ 10% coconut oil) with a major increase in the cholesterol content of IDL and LDL particles. The elevated IDL/ LDL level ofLDLR-I-mice was reduced to normal 4 d after the intravenous injection of a recombinant replication-defective adenovirus encoding the human LDL receptor driven by the cytomegalovirus promoter. The virus restored expression of LDL receptor protein in the liver and increased the clearance of 125I-VLDL. We conclude that the LDL receptor is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice and that adenovirusencoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency. (J. Clin. Invest. 1993. 92:883-893.)

Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angio-genesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis.Tumor cell invasion and metastatic processes require the coordinated and temporal regulation of a series of adhesive, proteolytic and migratory events 1 . The plasminogen activator (PA)-plasmin proteolytic system has been implicated in these processes. Urokinase-type (uPA) and tissue-type (tPA) plasminogen activators are serine proteases that catalyze the conversion of inactive plasminogen into plasmin, a broadly acting enzyme able to degrade a variety of extracellular matrix proteins and to activate metalloproteinases and growth factors 2,3 . Plasminogen and uPA bind to their specific receptors directing plasmin activity to the migrating tumor cell surface. The activities of PA are directly controlled by specific inhibitors, the PA inhibitors 1 and 2 (PAI1 and PAI2) (ref. 4).Many studies have focused on the role of uPA in cellular invasion and metastasis. Much of the data supporting the role of uPA in these events derives from in vitro and in vivo experiments demonstrating a correlation between uPA expression and cell invasion and metastasis as well as reduction of metastatic potential by using natural or synthetic serine protease inhibitors, neutralizing antibodies to uPA or antisense oligonucleotides 5,6 . PAI1 may also be directly involved in cancer progression. Both tumor cells and capillary endothelial cells express higher levels of PAI1 than other cell types [7][8][9] . Surprisingly, this inhibitor is necessary for optimal invasion of cultured lung cancer cells 10 , and an increasing number of clinical studies have demonstrated that high PAI1 levels indicate a poor prognosis for the survival of patients suffering from a variety of cancers [11][12][13] . However, as PAI1 is an acute-phase reactant 14 , it remains undetermined whether the increased PAI1 levels causally contribute to, or rather are the consequence of, the malignancy.Various observations indicate that the PA system may provide both surface-associated protease activity and an adhesion mechanism for cells through interaction with vitronectin. Deng et al. suggested that the balance between cell adhesion and cell detachment is governed by PAI1 (ref. 15). The PAI1-mediated release of cells attached to vitronectin seems to occur independently of the abili...