**2.8 Involvement of the immune system**

Innate immune cells play a crucial role in the pathogenesis of NAFLD [5]. Although the innate immune system is activated and proinflammatory monocytes are recruited into the liver in NASH, the precise signals that result from this are still poorly understood [17, 18]. Increased FFA levels, which result in lipotoxicity, insulin resistance, dysfunctional peripheral adipose tissue, and endotoxins originating from the gut, contribute to activating and maintaining the synthesis and release of pro-inflammatory cytokines in the liver at both local and systemic levels. JNK-AP-1 and IKK-NF-kB are two major inflammatory pathways that play a crucial role in the emergence of the chronic inflammatory state in NAFLD [6]. *In vitro* experiments employing cultured HepG2 cells and primary mouse, hepatocytes show that the release of damage-associated molecular patterns (DAMPs) from hepatocytes activates innate immune cells, especially macrophages (Kupffer cells). Additionally, several specific DAMPs, including high-mobility-group protein box 1 (HMGB1), have been demonstrated to activate TLR4 in NASH and NAFLD, playing a crucial role in the initial setting of NAFLD. In humans, other DAMPs, such as sonic hedgehog (SHH) ligands, have also been linked to the development of NAFLD and fibrosis. Another important component of NAFLD and NASH is neutrophils. The protease neutrophil elastase (NE), which is synthesized by neutrophils, secretes cellular IR, while deletion of NE results in less tissue inflammation [5]. Increased concentration of blood from the gut to the portal vein exposed the liver to gut-derived endotoxin, leading to endotoxemia, which activates Kupffer cells through the TLR4 complex on the cell surface. The Toll-like family of pattern recognition receptors are crucial for host defense against invading pathogens. When endotoxin interacts with TLR-4, a variety of proinflammatory mediators are released, leading to hepatic fibrosis and damage. Furthermore, cytokines have a significant impact on lipid metabolism [19]. Chitotriosidase (CHIT), an enzyme from the glycosylhydrolase family, is one of the mechanisms associated with the immune response in NASH and NAFLD. The CHIT gene spans around 20 kb of genomic DNA and is found on chromosome 1q31–q32 and has 12 exons. The majority of freshly generated 50 kDa CHIT is secreted by tissue macrophages, and a subsequent step cleaves the enzyme to secrete the active form of CHIT (39 kDa). Pathological tissue macrophages massively express CHIT in many conditions. In humans, NASH patients have much greater levels of CHIT expression than NAFLD patients or control subjects, which indicates a direct relationship between CHIT expression and the severity of NASH. Hence, patients with NASH had greater plasma levels of CHIT activity than those with NAFLD [20].
