We showed that clearance of HCV improves insulin resistance, beta-cell function, and hepatic IRS1/2 expression.

Abstract-Diseases linked to the elastin gene arise from loss-of-function mutations leading to protein insufficiency (supravalvular aortic stenosis) or from missense mutations that alter the properties of the elastin protein (dominant cutis laxa). Modeling these diseases in mice is problematic because of structural differences between the human and mouse genes. To address this problem, we developed a humanized elastin mouse with elastin production being controlled by the human elastin gene in a bacterial artificial chromosome. The temporal and spatial expression pattern of the human transgene mirrors the endogenous murine gene, and the human gene accurately recapitulates the alternative-splicing pattern found in humans. Human elastin protein interacts with mouse elastin to form functional elastic fibers and when expressed in the elastin haploinsufficient background reverses the hypertension and cardiovascular changes associated with that phenotype. Elastin from the human transgene also rescues the perinatal lethality associated with the null phenotype. The results of this study confirm that reestablishing normal elastin levels is a logical objective for treating diseases of elastin insufficiency such as supravalvular aortic stenosis. This study also illustrates how differences in gene structure and alternative splicing present unique problems for modeling human diseases in mice. (Circ Res. 2007;101:523-531.)Key Words: elastin Ⅲ supravalvular aortic stenosis Ⅲ vascular disease Ⅲ transgenic mice M utations within the elastin gene lead to several elastinopathies in humans that affect large blood vessels, the skin, and the lung. For example, loss-of-function mutations that produce haploinsufficiency have been linked to supravalvular aortic stenosis (SVAS-MIM185500), a congenital narrowing of the ascending aorta and other vessels. SVAS can occur sporadically or as a familial condition with autosomaldominant inheritance. 1 More than 50 different mutations have been described that lead to isolated SVAS. [2][3][4][5][6][7] SVAS is also a component of Williams-Beuren syndrome (WBS-MIM194050), 3,8 a frequent heterozygous deletion of a Ϸ1.6 Mb segment at chromosome 7q11.23 that includes the elastin gene. 3 In contrast to the loss-of-function mutations typical of SVAS, evidence suggests that autosomal dominant cutis laxa (ADCL-MIM123700) occurs through a dominant-negative mechanism. ADCL is characterized by lax skin with other internal organ involvement. Most elastin mutations associated with this disease are single nucleotide deletions near the 3Ј end of the gene 9 -11 resulting in missense sequence that alters the character of a biologically important domain at the end of the tropoelastin molecule. 12 ELN has also been suggested to be a susceptibility gene for hypertension, 13 emphysema, 14 and intracranial aneurysms. 15 ELN encodes a protein made up of alternating hydrophobic and crosslinking domains. 16 This repeating arrangement reflects the exon structure of the gene, with each type of domain encoded by distinct exon...

Shifren A, Durmowicz AG, Knutsen RH, Hirano E, Mecham RP. Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema.

Background: A humanized mouse was developed to study elastin assembly and the pathogenesis of cutis laxa. Results: Mutant transcripts incorporate into elastic fibers of skin and lung with adverse effects but not aorta. Conclusion: Elastin frameshift mutations alter elastin assembly domains. Significance: The mechanism of elastic fiber assembly may not be the same in all tissues.

Non-alcoholic steatohepatitis (NASH) is a severe form of fatty liver disease that is defined by the presence of inflammation and fibrosis, ultimately leading to cirrhosis and hepatocellular carcinoma. Treatment with human placental extract (HPE) reportedly ameliorates the hepatic injury. We evaluated the effect of HPE treatment in a mouse model of NASH. In the methione- and choline-deficient (MCD) diet-induced liver injury model, fibrosis started from regions adjacent to the sinusoids. We administered the MCD diet with high-salt loading (8% NaCl in the drinking water) to mice deficient in the vasoprotective molecule RAMP2 for 5 weeks, with or without HPE. In both the HPE and control groups, fibrosis was seen in regions adjacent to the sinusoids, but the fibrosis was less pronounced in the HPE-treated mice. Levels of TNF-α and MMP9 expression were also significantly reduced in HPE-treated mice, and oxidative stress was suppressed in the perivascular region. In addition, HPE dose-dependently increased survival of cultured endothelial cells exposed to 100 μM H2O2, and it upregulated expression of eNOS and the anti-apoptotic factors bcl-2 and bcl-xL. From these observations, we conclude that HPE ameliorates NASH-associated pathologies by suppressing inflammation, oxidative stress and fibrosis. These beneficially effects of HPE are in part attributable to its protective effects on liver sinusoidal endothelial cells. HPE could thus be an attractive therapeutic candidate with which to suppress progression from simple fatty liver to NASH.