The Crosstalk between Fat Homeostasis and Liver Regional Immunity in NAFLD

Figure 1

Crosstalk between hepatocytes, hepatic nonparenchymal cells, and ncRNA during the pathology of NAFLD. (1) Hepatic steatosis. Obesity and LPS from the intestine promote the release of proinflammatory cytokines TNF-α and IL-6 from KCs and adipocytes, which interact with ligands on the hepatocyte membrane. TNF-α activates SREBP-1c via the JAK/STAT3/SOCS-3 pathway, which activates FASN and ACC to promote hepatic TG accumulation. IL-6 upregulates IL-6 and SOCS-3 by NIK/NF-κB. The FFAs released from the FFA pool in the adipocytes directly activate PPARγ, which upregulates SREBP-1c to promote TG accumulation through other pathways. IR causes liver overload of glucose and insulin, and glucose activates ChREBP, which not only activates FASN and ACC but also activates SREBP-1c. Eventually, TG overload in hepatocytes causes hepatic steatosis. (2) NASH. Deregulation of adipocytes causes an increase in leptin levels, but adiponectin levels decrease. Decreased adiponectin causes a decrease in the release of the anti-inflammatory factor IL-10 from KCs, thereby promoting inflammation. TG overload causes excessive mitochondrial β-oxidation, which produces large amounts of ROS, which causes OS, causing KCs to release large amounts of proinflammatory factors (TNF-α, IL-6, and TGF-β) and FasL. Upon recognition of TNF-α and FasL with ligands on the hepatocyte membrane, they induce the formation of a death-inducing signaling complex (DISC), which induces hepatocyte apoptosis via the caspase pathway. Leptin can promote the release of TGF-β by KCs. After binding of TGF-β to ligand recognition on HSCs, liver fibrosis is promoted through the SMAD/Col-1 pathway. Lipids can induce NK and NKT release of apoptotic factors IFN-γ, FasL, and TNF-α. Activated NKT activates DCs, which produce IL-12 that stimulates NKT and ultimately aggravates inflammation and apoptosis. microRNA-373 (miR-373) reduces inflammation by inhibiting the AKT-mTOR-S6K signaling pathway, which inhibits IL-6 production; miR-7a upregulates YY1, which induces the expression of PPARγ by inhibiting the expression of CHOP-10, leading to the accumulation of FFAs and triglyceride, and finally causing NASH; MiR-130a-3p promotes the apoptosis of HSCs and inhibits the production of collagen by inhibiting the TGF-β/SMAD signaling pathway, thereby improving the pathological process of the liver; miR-26a improves NAFLD by partially reducing IL-6 expression; MiR-146a-5p inhibits the activity and proliferation of HSCs by downregulating Wnt1 and Wnt5a, and the amount of Col-1 is decreased, thereby inhibiting the occurrence of fibrosis in the progression of NAFLD; lncRNA SRA aggravates hepatic steatosis by reducing mitochondrial β-oxidation. lncRNA MALAT1 upregulates its target C-X-C motif chemokine ligand 5 (CXCL5), promoting the development of inflammation and fibrosis in NASH; and lncRNA NONRATT013819.2 promotes fibrosis by upregulating the expression of lysyl oxidase (Lox).