Different stages of pathophysiological conditions, starting from NAFLD to HCC, can be characterized based on the biological and molecular aspect (Panel A). The molecular understanding of multifactorial NAFLD pathogenesis (panel B) (IMAGE)
Caption
The progression of NAFLD pathogenesis is multifactorial, in which several molecular pathways are involved. The high FFA flux generated by WATs resulted in the functional modulation of hepatocytes by reducing the β-oxidation, and increasing the Krebs cycle and gluconeogenesis. It causes low ATP production, mitochondrial dysfunction, and ER stress. In this context, the high TG and VLDL signature the pathophysiological state of the disease. Insulin stress mediates the increase in glycogenesis and de novo lipogenesis inside the hepatocyte. The genetic variation of PNPLA3 effects the hepatic TG hydrolyzation. The less biosynthesis of carnitine resulted in the low transportation of fatty acids to the mitochondria for β-oxidation. The high insulin level promoted the SREBP1-c upregulation, and increased the fatty acids in hepatocytes. As the uncoupling of the electron transport chain took place, the superoxide produced by NADPH oxidase induced liver injury. In addition, gut commensal-released products, such as LPS, lactose and ethanol, contributed to the NAFLD pathogenesis. The symbols “↑”, “↓”, and “┴” refer to “high”, “low”, and “inhibition”, respectively. ATP, Adenosine triphosphate; ChREBP, carbohydrate response element binding protein; CPT2, carnitine palmitoyltransferase 2; e−, electron; ER, endoplasmic reticulum; FATP, fatty acid-transport protein 1; FFA, free fatty acids; GLUT, glucose transporter; HCC, hepatocellular carcinoma; IR, insulin receptor; IRS, insulin receptor substrate; IRS1, Insulin receptor substrate 1; LPS, lipopolysaccharide; LXR, liver X receptor; NADP, nicotinamide adenine dinucleotide phosphate; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PNPLA3, patatin-like phospholipase domain-containing protein 3; OCTN2, organic cation transporter; PPARγ, peroxisome proliferator- activated receptor gamma; ROS, reactive oxygen species; SREBP1c, sterol regulatory element binding protein 1; TG, triglyceride; TNFα, tumor necrosis factor alpha; WAT, white adipose tissue; VLDL, very low-density lipoprotein.
Credit
Subendu Sarkar
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