Emerging data highlight the critical role for the innate immune system in the progression of nonalcoholic fatty liver disease (NAFLD). Connexin 32 (Cx32), the primary liver gap junction protein, is ...capable of modulating hepatic innate immune responses and has been studied in dietary animal models of steatohepatitis. In this work, we sought to determine the association of hepatic Cx32 with the stages of human NAFLD in a histologically characterized cohort of 362 patients with NAFLD. We also studied the hepatic expression of the genes and proteins known to interact with Cx32 (known as the connexome) in patients with NAFLD. Last, we used three independent dietary mouse models of nonalcoholic steatohepatitis to investigate the role of Cx32 in the development of steatohepatitis and fibrosis. In a univariate analysis, we found that Cx32 hepatic expression associates with each component of the NAFLD activity score and fibrosis severity. Multivariate analysis revealed that Cx32 expression most closely associated with the NAFLD activity score and fibrosis compared to known risk factors for the disease. Furthermore, by analyzing the connexome, we identified novel genes related to Cx32 that associate with NAFLD progression. Finally, we demonstrated that Cx32 deficiency protects against liver injury, inflammation, and fibrosis in three murine models of nonalcoholic steatohepatitis by limiting initial diet‐induced hepatoxicity and subsequent increases in intestinal permeability. Conclusion: Hepatic expression of Cx32 strongly associates with steatohepatitis and fibrosis in patients with NAFLD. We also identify novel genes associated with NAFLD and suggest that Cx32 plays a role in promoting NAFLD development. (Hepatology Communications 2018;2:786‐797)
Rapid advances in genetics have led to an increased understanding of the genetic determinants of human disease, including many gastrointestinal (GI) disorders. Coupled with a proliferation of genetic ...testing services, this has resulted in a clinical landscape where commercially available genetic tests for GI disorders are now widely available. In this review, we discuss the current status of clinical genetic testing for GI illnesses, review the available testing options, and briefly discuss indications for and practical aspects of such testing. Our goal is to familiarize the practicing gastroenterologist with this rapidly changing and important aspect of clinical care.
One serious side effect of statin drugs is skeletal muscle myopathy. Although the mechanism(s) responsible for statin myopathy remains to be fully determined, an increase in muscle atrophy gene ...expression and changes in mitochondrial content and/or function have been proposed to play a role. In this study, we examined the relationship between statin-induced expression of muscle atrophy genes, regulators of mitochondrial biogenesis, and markers of mitochondrial content in slow- (ST) and fast-twitch (FT) rat skeletal muscles. Male Sprague Dawley rats were treated with simvastatin (60 or 80 mg·kg.sup.-1 ·day.sup.-1) or vehicle control via oral gavage for 14 days. In the absence of overt muscle damage, simvastatin treatment induced an increase in atrogin-1, MuRF1 and myostatin mRNA expression; however, these were not associated with changes in peroxisome proliferator gamma co-activator 1 alpha (PGC-1alpha) protein or markers of mitochondrial content. Simvastatin did, however, increase neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS) and AMPK alpha-subunit protein expression, and tended to increase total NOS activity, in FT but not ST muscles. Furthermore, simvastatin induced a decrease in beta-hydroxyacyl CoA dehydrogenase (beta-HAD) activity only in FT muscles. These findings suggest that the statin-induced activation of muscle atrophy genes occurs independent of changes in PGC-1alpha protein and mitochondrial content. Moreover, muscle-specific increases in NOS expression and possibly NO production, and decreases in fatty acid oxidation, could contribute to the previously reported development of overt statin-induced muscle damage in FT muscles.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In a variety of human genetic diseases, replacement of the absent or defective protein provides significant therapeutic benefits. As a model for a somatic cell gene therapy system, cultured murine ...fibroblasts were transfected with a human growth hormone (hGH) fusion gene and cells from one of the resulting clonal lines were subsequently implanted into various locations in mice. Such implants synthesized and secreted hGH, which was detectable in the serum. The function of the implants depended on their location and size, and on the histocompatibility of the donor cells with their recipients. The expression of hGH could be modified by addition of regulatory effectors, and, with appropriate immunosuppression, the implants survived for more than 3 months. This approach to gene therapy, here termed ``transkaryotic implantation,'' is potentially applicable to many genetic diseases in that (i) the transfected cell line can be extensively characterized prior to implantation, (ii) several anatomical sites are suitable for implantation, and (iii) regulated expression of the gene of therapeutic interest can be obtained.
A new MOS gate-controlled power switch with a very low on-resistance is described. The fabrication process is similar to that of an n-channel power MOSFET but employs an n - -epitaxial layer grown on ...a p + substrate. In operation, the epitaxial region is conductivity modulated (by excess holes and electrons) thereby eliminating a major component of the on-resistance. For example, on-resistance values have been reduced by a factor of about 10 compared with those of conventional n-channel power MOSFET's of comparable size and voltage capability.
Insulin is a polypeptide hormone of major physiological importance in the regulation of fuel homeostasis in animals (reviewed in refs 1,2). It is synthesized by the beta-cells of pancreatic islets, ...and circulating insulin levels are regulated by several small molecules, notably glucose, amino acids, fatty acids and certain pharmacological agents. Insulin consists of two polypeptide chains (A and B, linked by disulphide bonds) that are derived from the proteolytic cleavage of proinsulin, generating equimolar amounts of the mature insulin and a connecting peptide (C-peptide). Humans, like most vertebrates, contain one proinsulin gene, although several species, including mice and rats, have two highly homologous insulin genes. We have studied the regulation of serum insulin levels and of insulin gene expression by generating a series of transgenic mice containing the human insulin gene. We report here that the human insulin gene is expressed in a tissue-specific manner in the islets of these transgenic mice, and that serum human insulin levels are properly regulated by glucose, amino acids and tolbutamide, an oral hypoglycaemic agent.
PDF
