**2.3 Insulin resistance**

In healthy individuals, insulin receptor substrates (IRS), among other substrates, are phosphorylated when it binds to its receptor, which transmits the insulin signal [4]. Insulin resistance is among the major causes of NAFLD, which increases hepatic lipogenesis and inhibits adipose tissue lipolysis, resulting in an enhanced influx of fatty acids into the liver. Hepatocytes store fat mostly in the form of triglycerides generated by the esterification of glycerol and FFAs. Hepatic accumulation of triglyceride functions as a defense mechanism to balance off the excess FFAs in the plasma rather than as a hepatotoxic event. However, diacylglycerol (DAG) and other bioactive intermediates, such as ceramides, can cause lipotoxicity, which may progress to

inflammation, necrosis, and hepatic fibrosis [12]. When the mechanisms protecting hepatocytes against lipotoxicity are depleted, NAFLD develops into NASH. This causes necrosis, secondary repair processes, and accumulation of scar collagen tissue, which are controlled by hepatic stellate cells, leading to the progress and development of hepatic fibrosis. Insulin resistance is also associated with hyperinsulinemia, which can result in the upregulation of transcription factor sterol regulatory element binding protein-1c (SREBP-1c), a major transcriptional regulator of genes involved in DNL and the inhibition of FFA's β-oxidation, which could further promote the deposition of hepatic lipids. Several anomalies investigated in NAFLD inhibit the insulin signaling pathway, which in turn causes IR. Elevated lipid metabolites, including diacylglycerol (DAG), have been linked to a protein kinase C (PKC) dependent process that blocks insulin receptor activation and insulin signaling modifies IRS-2 phosphorylation [13].
