Molecular basis of progressive familial intrahepatic cholestasis 3. A proteomics study.

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe rare liver disease that affects between 1/50,000 and 1/100,000 children. In physiological conditions, bile is produced by the liver and stored in the gallbladder, and then it flows to the small intestine to play its role in fat digestion. To prevent tissue damage, bile acids (BAs) are kept in phospholipid micelles.

Prevalence and predictors of non-alcoholic steatohepatitis in patients with morbid obesity.

Background: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in morbid obesity (MO). A considerable proportion of patients with MO have non-alcoholic steatohepatitis (NASH). Liver biopsy (LB) is the only procedure that reliably differentiates NASH from other stages of NAFLD, but its invasive nature prevents it from being generalisable.

Insulin Prevents Hypercholesterolemia by Suppressing 12α-Hydroxylated Bile Acids.

Background: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies.

Methods: To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1.

Prevalence and predictors of non-alcoholic steatohepatitis in patients with morbid obesity.

Background: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in morbid obesity (MO). A considerable proportion of patients with MO have non-alcoholic steatohepatitis (NASH). Liver biopsy (LB) is the only procedure that reliably differentiates NASH from other stages of NAFLD, but its invasive nature prevents it from being generalisable.

Performance of Noninvasive Liver Fibrosis Scores in the Morbid Obese Patient, Same Scores but Different Thresholds.

Introduction: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. It is a spectrum of progressive alterations, with the final step in liver fibrosis which carries a high burden of long-term mortality. The scores used to predict liver fibrosis are not properly validated in morbid obesity (MO).

Peripheral Atherosclerosis in Patients With Erectile Dysfunction: A Population-Based Study.

Introduction: The presence of erectile dysfunction (ED) could be a warning of vascular disease in different arterial territories.

Aim: The aim of this study was to investigate the association between ED and the presence of atherosclerosis in 2 different vascular beds: carotid and lower limbs.

Methods: A total of 614 volunteers between 45 and 74 years of age (mean age 61.

Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis.

Despite the well-documented association between insulin resistance and cardiovascular disease, the key targets of insulin relevant to the development of cardiovascular disease are not known. Here, using non-biased profiling methods, we identify the enzyme flavin-containing monooxygenase 3 (Fmo3) to be a target of insulin. FMO3 produces trimethylamine N-oxide (TMAO), which has recently been suggested to promote atherosclerosis in mice and humans.

Liver upregulation of genes involved in cortisol production and action is associated with metabolic syndrome in morbidly obese patients.

Background: Hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, which converts cortisone (inactive) to cortisol, is downregulated in obesity. However, this compensation fails in obese with metabolic abnormalities, such as diabetes. To further characterize the tissue-specific cortisol regeneration in obesity, we have investigated the mRNA expression of genes related to local cortisol production, i.

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis.

Growth hormone (GH) secretion and serum insulin-like growth factor-I (IGF-I) decline with aging. This study addresses the role played by the hypothalamic regulators in the aging GH decline and investigates the mechanisms through which growth hormone secretagogues (GHS) activate GH secretion in the aging rats. Two groups of male Wistar rats were studied: young-adult (3 mo) and old (24 mo).

Pituitary alterations involved in the decline of growth hormone gene expression in the pituitary of aging rats.

Growth hormone (GH) declines during aging. This study investigates whether pituitary constitutive alterations may be involved in the GH decline. Two groups of male Wistar rats were studied (young: 3-month-old; old: 24-month-old).

Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization.

Both insulin and IGF-1 have been implicated in control of retinal endothelial cell growth, neovascularization, and diabetic retinopathy. To precisely define the role of insulin and IGF-1 signaling in endothelium in these processes, we have used the oxygen-induced retinopathy model to study mice with a vascular endothelial cell-specific knockout of the insulin receptor (VENIRKO) or IGF-1 receptor (VENIFARKO). Following relative hypoxia, VENIRKO mice show a 57% decrease in retinal neovascularization as compared with controls.

Elevated plasma levels of the atherogenic mediator soluble CD40 ligand in diabetic patients: a novel target of thiazolidinediones.

Background: Considerable evidence implicates the proinflammatory cytokine CD40 ligand (CD40L) in atherosclerosis and accumulating data link type 1 and 2 diabetes, conditions associated with accelerated atherosclerosis, to inflammation. This study therefore evaluated the hypothesis that diabetic patients have elevated plasma levels of soluble CD40L (sCD40L) and that treatment with the insulin-sensitizing thiazolidinediones lowers this index of inflammation.

Methods And Results: Subjects with type 1 (n=49) or type 2 diabetes (n=48) had higher (P<0.

The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance.

Insulin receptors (IRs) on vascular endothelial cells have been suggested to participate in insulin-regulated glucose homeostasis. To directly address the role of insulin action in endothelial function, we have generated a vascular endothelial cell IR knockout (VENIRKO) mouse using the Cre-loxP system. Cultured endothelium of VENIRKO mice exhibited complete rearrangement of the IR gene and a more than 95% decrease in IR mRNA.

Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase.

On the basis of ex vivo studies using insulin-responsive cells, activation of a Class IA phosphoinositide 3-kinase (PI3K) seems to be required for a wide variety of cellular responses downstream of insulin. The Class IA PI3K enzymes are heterodimers of catalytic and regulatory subunits. In mammals, insulin-responsive tissues express both the p85alpha and p85beta isoforms of the regulatory subunit.