RESUMO
BACKGROUND/OBJECTIVES: Non-alcoholic steatohepatitis (NASH) is a serious liver condition, closely associated with obesity and insulin resistance. Recent studies have suggested an important role for inflammasome/caspase-1 in the development of NASH, but the potential therapeutic value of caspase-1 inhibition remains unclear. Therefore, we aimed to investigate the effects of caspase-1 inhibition in the ongoing disease process, to mimic the clinical setting. SUBJECTS/METHODS: To investigate effects of caspase-1 inhibition under therapeutic conditions, male LDLR-/-.Leiden mice were fed a high-fat diet (HFD) for 9 weeks to induce a pre-diabetic state before start of treatment. Mice were then continued on HFD for another 12 weeks, without (HFD) or with (HFD-YVAD) treatment with the caspase-1 inhibitor Ac-YVAD-cmk (40 mg kg(-1) per day). RESULTS: Nine weeks of HFD feeding resulted in an obese phenotype, with obesity-associated hypertriglyceridemia, hypercholesterolemia, hyperglycemia and hyperinsulinemia. Treatment with Ac-YVAD-cmk did not affect further body weight gain or dyslipidemia, but did attenuate further progression of insulin resistance. Histopathological analysis of livers clearly demonstrated prevention of NASH development in HFD-YVAD mice: livers were less steatotic and neutrophil infiltration was strongly reduced. In addition, caspase-1 inhibition had a profound effect on hepatic fibrosis, as assessed by histological quantification of collagen staining and gene expression analysis of fibrosis-associated genes Col1a1, Acta2 and Tnfa. CONCLUSIONS: Intervention with a caspase-1 inhibitor attenuated the development of NASH, liver fibrosis and insulin resistance. Our data support the importance of inflammasome/caspase-1 in the development of NASH and demonstrate that therapeutic intervention in the already ongoing disease process is feasible.
Assuntos
Hiperinsulinismo/tratamento farmacológico , Resistência à Insulina , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Serpinas/uso terapêutico , Proteínas Virais/uso terapêutico , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Dislipidemias/complicações , Dislipidemias/etiologia , Dislipidemias/metabolismo , Hiperinsulinismo/complicações , Hiperinsulinismo/patologia , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Obesidade/etiologia , Obesidade/metabolismo , Serpinas/farmacologia , Proteínas Virais/farmacologiaRESUMO
The molecular biology dogma that DNA replicates its genetic information within nucleotide sequences and transcribes it to RNA where it codes for the generation of mRNA, failed to consider a significant part of the genetic code. Although it has been generally assumed that most genetic information is executed by proteins, recent evidence suggests that the majority of the genomes of mammals and other complex organisms is transcribed into non-coding RNA (ncRNA), many of which are alternatively spliced and/or processed into smaller functional RNA molecules. ncRNAs are predominantly involved in processes that require highly specific nucleic acid recognition, revealing a, so far hidden, layer of internal signals that control various levels of gene expression in developmental and (patho)physiological processes. MicroRNAs (miRNAs) are a large class of evolutionary conserved, small ncRNAs, typically 18 to 24 nucleotides in length, that primarily function at the posttranscriptional level by interacting with the 3' untranslated region (UTR) of specific target mRNAs in a sequence-specific manner. Despite the advances in miRNA discovery, the role of miRNAs in physiological and pathological processes is just rising, revealing their cellular functions in proliferation and differentiation, apoptosis, the stress response and tumorgenesis. MiRNA expression profiling and the manipulation of their expression in cardiac tissue has led to the discovery of regulatory roles for these small ncRNAs during cardiac development and disease, implicating them in regulation of cardiac gene expression. Here we review the basic mechanisms by which cardiovascular miRNAs are regulated in the larger context of cardiogenesis and in cardiovascular disease.