RESUMO
Nonalcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma in their advanced stages; however, there are currently no approved therapies. Here, we show that microRNA (miR)-33b in hepatocytes is critical for the development of NASH. miR-33b is located in the intron of sterol regulatory element-binding transcription factor 1 and is abundantly expressed in humans, but absent in rodents. miR-33b knock-in (KI) mice, which have a miR-33b sequence in the same intron of sterol regulatory element-binding transcription factor 1 as humans and express miR-33b similar to humans, exhibit NASH under high-fat diet feeding. This condition is ameliorated by hepatocyte-specific miR-33b deficiency but unaffected by macrophage-specific miR-33b deficiency. Anti-miR-33b oligonucleotide improves the phenotype of NASH in miR-33b KI mice fed a Gubra Amylin NASH diet, which induces miR-33b and worsens NASH more than a high-fat diet. Anti-miR-33b treatment reduces hepatic free cholesterol and triglyceride accumulation through up-regulation of the lipid metabolism-related target genes. Furthermore, it decreases the expression of fibrosis marker genes in cultured hepatic stellate cells. Thus, inhibition of miR-33b using nucleic acid medicine is a promising treatment for NASH.
Assuntos
Neoplasias Hepáticas , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Camundongos , Humanos , Animais , Hepatopatia Gordurosa não Alcoólica/genética , Antagomirs , MicroRNAs/genética , MicroRNAs/metabolismo , Colesterol , Neoplasias Hepáticas/patologia , Fatores de TranscriçãoRESUMO
Adaptive thermogenesis is essential for survival, and therefore is tightly regulated by a central neural circuit. Here, we show that microRNA (miR)-33 in the brain is indispensable for adaptive thermogenesis. Cold stress increases miR-33 levels in the hypothalamus and miR-33-/- mice are unable to maintain body temperature in cold environments due to reduced sympathetic nerve activity and impaired brown adipose tissue (BAT) thermogenesis. Analysis of miR-33f/f dopamine-ß-hydroxylase (DBH)-Cre mice indicates the importance of miR-33 in Dbh-positive cells. Mechanistically, miR-33 deficiency upregulates gamma-aminobutyric acid (GABA)A receptor subunit genes such as Gabrb2 and Gabra4. Knock-down of these genes in Dbh-positive neurons rescues the impaired cold-induced thermogenesis in miR-33f/f DBH-Cre mice. Conversely, increased gene dosage of miR-33 in mice enhances thermogenesis. Thus, miR-33 in the brain contributes to maintenance of BAT thermogenesis and whole-body metabolism via enhanced sympathetic nerve tone through suppressing GABAergic inhibitory neurotransmission. This miR-33-mediated neural mechanism may serve as a physiological adaptive defense mechanism for several stresses including cold stress.
Assuntos
MicroRNAs/metabolismo , Sistema Nervoso Simpático/fisiologia , Termogênese/genética , Tecido Adiposo Marrom/fisiologia , Animais , Temperatura Corporal/fisiologia , Peso Corporal , Encéfalo/metabolismo , Linhagem Celular , Temperatura Baixa , Dieta Hiperlipídica , Estresse do Retículo Endoplasmático , Humanos , Integrases/metabolismo , Masculino , Camundongos , Camundongos Obesos , MicroRNAs/genética , Consumo de Oxigênio/fisiologia , Fenótipo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismoRESUMO
Recently, advances in genomic technology such as RNA sequencing and genome-wide profiling have enabled the identification of considerable numbers of non-coding RNAs (ncRNAs). MicroRNAs have been studied for decades, leading to the identification of those with disease-causing and/or protective effects in vascular disease. Although other ncRNAs such as long ncRNAs have not been fully described yet, recent studies have indicated their important functions in the development of vascular diseases. Here, we summarize the current understanding of the mechanisms and functions of ncRNAs, focusing on microRNAs, circular RNAs and long ncRNAs in vascular diseases.
Assuntos
RNA não Traduzido/metabolismo , Doenças Vasculares/metabolismo , Humanos , RNA não Traduzido/genética , Doenças Vasculares/genéticaRESUMO
BACKGROUND: About 7% of amyloid A (AA) amyloidosis cases are accompanied by heart disease. Although several studies have recently reported that specific biologicals improved renal function in AA amyloidosis, little evidence is available regarding heart disease in AA amyloidosis. CASE SUMMARY: A 57-year-old woman with rheumatoid arthritis presented with sudden worsening of renal function. Echocardiography revealed granular sparkling appearance in the ventricular septum and posterior wall (PW). Echocardiography indicated left ventricular (LV) diastolic dysfunction. Global longitudinal strain (GLS) exhibited an apical sparing pattern. Cardiac biopsy demonstrated amyloid A deposition on immunostaining. Soluble tumour necrosis factor-alpha receptor etanercept therapy was initiated. Four years later, echocardiography showed improved diastolic function, including E/A and E/e', and decreased wall thickness in both the interventricular septum and PW of the left ventricle. Granular sparkling appearance had diminished. Moreover, the LV dysfunction improved on GLS. Five years later, the medication was gradually losing effect and the patient had worsening pain in the joints; moreover, articular destruction was observed on radiography. The patient was switched to abatacept therapy. Echocardiography showed recurrence of LV hypertrophy and electrocardiogram showed down-sloped ST depression in V4-6 leads. DISCUSSION: This case indicates that etanercept can be effective for heart disease in AA amyloidosis. Of particular, interest is the improvement of granular sparkling appearance in addition to cardiac function improvement noted in this case.
