Skeletal muscle miR-34a/SIRT1:AMPK axis is activated in experimental and human non-alcoholic steatohepatitis

AbstractNon-alcoholic fatty liver disease (NAFLD) pathogenesis associates with intramyocellular lipid deposition and mitochondrial dysfunction. microRNAs (miRs), including pro-apoptotic miR-34a, are modulated during disease progression in liver tissue and plasma. We aimed to investigate the functional role of the miR-34a/SIRT1:AMP-activated protein kinase (AMPK) pathway in modulating local mitochondrial dysfunction in the skeletal muscle of human and experimental non-alcoholic steatohepatitis. Muscle biopsies were obtained from morbid obese NAFLD patients undergoing bariatric surgery. C57BL/6N mice were fed different NAFLD-inducing diets and C2C12 muscle cells incubated with palmitic acid (PA) in the presence or absence of an AMPK activator, or upon miR-34a functional modulation. Several muscle miRNAs, including miR-34a, were found increased with human NAFLD progression. Activation of the miR-34a/SIRT1:AMPK pathway, concomitant with impairment in insulin signalling mediators and deregulation of mitochondrial-shaping proteins, was evident in C2C12 cells incubated with PA, as well as in the skeletal muscle of all three diet-induced NAFLD mice models. Functional studies established the association between miR-34a- and PA-induced muscle cell deregulation. Of note, activation of AMPK almost completely prevented miR-34a- and PA-induced cellular stress. In addition, the miR-34a/SIRT1:AMPK pathway and mitochondrial dynamics dysfunction were also found amplified in muscle of human NAF...
Source: Journal of Molecular Medicine - Category: Molecular Biology Source Type: research

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nia Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent forms of chronic liver disorders among adults, children, and adolescents, and a growing epidemic, worldwide. Notwithstanding the known susceptibility factors for NAFLD, i.e., obesity and metabolic syndrome, the exact cause(s) of this disease and the underlying mechanisms of its initiation and progression are not fully elucidated. NAFLD is a multi-faceted disease with metabolic, genetic, epigenetic, and environmental determinants. Accumulating evidence shows that exposure to environmental toxicants contributes to the development of NAFLD by promo...
Source: International Journal of Environmental Research and Public Health - Category: Environmental Health Authors: Tags: Review Source Type: research
In conclusion, TSF improved lipid accumulation and hepatic steatosis by inducing the AMPK/SIRT1 pathway-mediated autophagy. Introduction Nonalcoholic fatty liver disease (NAFLD) has become a worldwide health concern due to the increased incidence of obesity and diabetes. In addition, NAFLD is closely associated with the risk factors of coronary heart disease, such as metabolic syndrome, diabetes mellitus, and dyslipidemia, which are considered to be the leading causes of death (Wiest et al., 2017). Although our understanding of the pathogenesis of NAFLD has significantly improved, there is still no effective medica...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
In this study, room temperature (RT) of 25°C was considered as control, and RT at 32°C for 8 h per day was set as the HS treatment. After 3 weeks, the intestinal contents of jejunum, ileum, and cecum were harvested to investigate the microbiota composition variations by 16S ribosomal RNA amplicon sequencing. And the weight gain, adipose indices, intestinal morphology, and a certain number of serum biochemical parameters were also measured and analyzed. The results showed the microbial species at different levels differentially enriched in duck jejunum and cecum under HS, while no significant data were observed in i...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
This study was approved by the University of Sydney Animal Ethics Committee (Protocol #2015/816). The experiments described herein were carried out according to the guidelines laid down by the New South Wales Animal Research Act and the 8th Edition of the Australian code for the care and use of animals for scientific purposes. Animal Characteristics Sample size for this study was calculated as follows: considering previous studies from our group (Martinez-Huenchullan et al., 2018) and that one of our main outcomes was muscle high-molecular weight (HMW) adiponectin, having a statistical significance of 0.05). In body comp...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
Ali Mahzari1, Songpei Li1, Xiu Zhou1,2, Dongli Li2, Sherouk Fouda1, Majid Alhomrani1, Wala Alzahrani1, Stephen R. Robinson1 and Ji-Ming Ye1,2* 1Lipid Biology and Metabolic Disease Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia 2School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China The present study investigated the effects of matrine on non-alcoholic steatohepatitis (NASH) in mice induced by a methionine choline-deficient (MCD) diet and the mechanism involved. The study was performed in C57B/6J mice fed a MCD diet for 6 weeks to induce NAS...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
In conclusion, FGF21 belongs to a promising class of cytokines that are induced in response to stress and that can be used as a drug, drug target, or through a biomarker, depending on the physio-pathological context. All these findings will become clear when FGF21 will be used as a therapeutic molecule, exploiting the beneficial effects of FGF21 for treating metabolic disease or when it will be blocked to ameliorate disease progression and the onset of disease. Author Contributions CT and MS wrote the manuscript. VR contributed to the discussion. Funding This work was supported from the AFM-Telethon (19524), Italian Mi...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
Conclusions: Bariatric surgery appears to be capable of partially reversing the obesity-related epigenome. The identification of potential epigenetic biomarkers predictive for the success of bariatric surgery may open new doors to personalized therapy for severe obesity. Introduction Obesity is currently a huge healthcare problem, worldwide, and is a risk factor for several diseases such as type 2 diabetes (T2D), cardiovascular disease and cancer (1). As the prevalence of obesity reaches pandemic proportions, this metabolic disease is estimated to become the biggest cause of mortality in the near future (2). In fact,...
Source: Frontiers in Endocrinology - Category: Endocrinology Source Type: research
In this study, we explore shared epigenetic mechanisms of the association between mtDNA content and insulin levels, supporting the developmental origins of this link. First, the association between cord blood insulin and mtDNA content in 882 newborns of the ENVIRONAGE birth cohort was assessed. Cord blood mtDNA content was established via qPCR, while cord blood levels of insulin were determined using electrochemiluminescence immunoassays. Then the cord blood DNA methylome and transcriptome were determined in 179 newborns, using the human 450K methylation Illumina and Agilent Whole Human Genome 8 × 60 K microarrays, r...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more. This content is...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Non-alcoholic fatty liver disease (NAFLD) is considered to be a potential new component of the metabolic syndrome (MetS) [1]. It is characterized by excessive flux of fatty acids (FA) and triglycerides (TG) accumulation in the liver, primarily activated by dietary factors, obesity and insulin resistance [2]. This results in increased inflammation and mitochondrial dysfunction in the liver, conditions that lead to fibrosis and cell apoptosis. Moreover, genetic and epigenetic factors, as well as gut microbiome dysfunction, further induce hepatic steatosis, inflammation and oxidative stress.
Source: Nutrition - Category: Nutrition Authors: Source Type: research
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