Abstract
Health issues associated with excessive caloric intake and sedentary lifestyle are driving a modern “epidemic” of liver disease. Initially presenting in the clinic as an excessive accumulation of fat within hepatocyte cells (steatosis), the progression to more severe non-alcoholic steatohepatitis (NASH) in which liver damage and inflammation are overt features, is becoming increasingly common. Often developing as a sequela of obesity, non-alcoholic fatty liver disease (NAFLD) arises in almost one-third of people initially carrying excess hepatic fat and is likely the result of the liver’s limited capacity to cope with the modern-day levels of dietary fatty acids circulating in the blood. While routine imaging can readily assess the presence and level of “extra-hepatic fat”, a proper diagnosis of disease progression to NASH is currently only possible by liver biopsy. A general reluctance to undergo such screening means that the prevalence of NASH is likely to be under reported and, thus, risk assessment for future metabolic syndrome (MetS) markedly compromised. The seemingly inevitable progression to overt insulin resistance that characterizes MetS may in part be the consequence of the body’s attempt to cope with NAFLD by driving systemic insulin sensitivity and, thus, fatty acid breakdown. The potential significance of miRNAs in both physiological homeostasis and pathogenesis is increasingly appreciated and in the liver may contribute specifically to the regulation of lipid pathways and NAFLD progression. As such, they may have utility as molecular indicators for the accurate profiling of both initial risk and disease progression from simple steatosis to NASH, and further to fibrosis/cirrhosis.
Highlights
Health issues associated with excessive caloric intake and sedentary lifestyle are driving a modern “epidemic” of liver disease
The pathological spectrum of non-alcoholic fatty liver disease (NAFLD) progresses to non-alcoholic steatohepatitis (NASH), which is defined by the additional degeneration of the hepatocytes and sinusoidal fibrosis [4,5] and, to end-stage cirrhosis, the main driver of liver transplant interventions [6,7]
We have found that circulating miR-335 is significantly decreased after weight loss in obese patients with T2DM who underwent gastric bypass (GBP) bariatric surgery and that this reduction in miR-335 level was strongly correlated with BMI [46]
Summary
A combination of dietary-based caloric excess and a sedentary lifestyle (confounded by socioeconomic factors) has led to population-wide weight gain and, subsequently, an increasing incidence of obesity-related comorbidities (e.g., non-alcoholic fatty liver (NAFLD), type 2 diabetes mellitus (T2DM). The abnormal accumulation of fat in the liver (occurring in the absence of significant alcohol consumption) is a defining characteristic of NAFLD and begins with the intra-cytoplasmic accumulation of TG as liposomes around the hepatocyte nucleus. Abnormally elevated hepatic FA biosynthesis can precipitate glucose intolerance and insulin resistance (IR) as a consequence of the systemic attempt to restore homeostasis by promoting fat turnover [9]. By driving lipolysis, this adaptive mechanism results in further increases in the circulating level of TG-derived free fatty acids (FFAs) [10]. The progression of liver disease often occurs in parallel with that of MetS
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