EC ENDOCRINOLOGY AND METABOLIC RESEARCH The Entangled Relationship between NAFLD, Insulin Resistance and Obesity (ERNIRO)

NAFLD - Prevalence and Associations: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent metabolic disorder having as key feature, the insulin resistance (IR), accompanied with impaired insulin sensitivity (IS) in liver and other organs including muscles and adipose tissues. Further, the incidence of NAFLD is high in conditions associated with IR such as obesity, type 2 diabetes mellitus (T2DM), dyslipidemia and metabolic syndrome (MetS). Intrahepatic triglyceride accumulation, or steatosis, is the hallmark of NAFLD that develops when the rate of fatty acids (FAs) influx (FAs uptake from plasma and de novo lipogenesis) exceeds the rate of FAs efflux (FA oxidation and secretion of triglycerides as VLDL). A subset of NAFLD patients go on to develop non-alcoholic steatohepatitis (NASH), which can progress to fibrosis and cirrhosis. the hits’ The first ‘hit’ is of FAs and triglyceride in hepatocytes (steatosis), and the second ‘hit’ is the of steatosis to NASH. with factors overnutrition, increased fat mass, endocrine disruptors and oxidant injury, proinflammatory cytokines and altered adipokines involved to variable extent. The pro-inflammatory cytokines appear to interfere with insulin signaling by activating various inflammatory pathways. The pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α), activate intracellular kinases such as JNK and IKKβ and the activation of downstream transcription factors like AP-1 and NF-κB results in the impairment of insulin receptor signaling. and The increased FAs may activate the intrinsic apoptosis pathway in hepatocytes via c-Jun N-terminal kinase (JNK), which promotes progression from simple steatosis to NASH and advanced hepatic fibrosis. The adipocyte secretome, including FFAs and adipokines, is closely linked to the evolution and progression of NAFLD. in the development of NAFLD, and possibly the hepatic steatosis caused by consumption of excess dietary fat contributes to the hepatic IR. The hyperinsu linemia and the hyperglycemia typically occur with obesity and promote DNL by upregulating lipogenic transcription factors, such as sterol regulatory element binding protein-1c (SREBP-1c) and carbohydrate response element binding protein (CREBP). Insulin-mediated activation of SREBP-1c increases malonyl-CoA, a key intermediate of the FA synthesis, which inhibits carnitine palmitoyl-transferase 1 and long chain FAs entry into the mitochondria for β-oxidation and thus favours hepatic triglyceride accumulation [14]. The Go to:Over the last decade, the understanding of the association between insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) has dramatically evolved. There is clear understanding that carriers of some common genetic variants, i.e., the patatin-like phospholipase do-main-containing 3 (PNPLA3) or the transmembrane 6 superfamily member 2 (TM6SF2) are at risk of developing severe forms of NAFLD even in the presence of reduced or absent IR. In contrast, there are obese patients with “metabolic” (non-genetically driven) NAFLD who present severe IR. Owing to the epidemic obesity and the high prevalence of these genetic variants in the general population, the number of pediatric cases with combination of genetic and metabolic NAFLD is expected to be very high. Gut dysbiosis, excessive dietary intake of saturated fats/fructose-enriched foods and exposure to some chemicals contribute all to both IR and NAFLD, adding further complex ity to the understanding of their relationship. Once NAFLD is established, IR can accelerate the progression to the more severe form of liver derangement that is the non-alcoholic steatohepatitis.Keywords: tive hepatic IR, characterized by disturbed insulin-mediated suppression of hepatic glucose output but intact stimulation of lipogenesis, contribute to the complex relationships by inducing lipogenic programming and systemic hyperlipidaemia and the