Fig. 8

Schematic diagram of the Ox-LDL uptake and lipid metabolism pathways of the hepatocytes. AAV8-TBG-LOX-1 induces hepatocyte-specific expression of LOX-1, and hepatocytes endocytose LDL and Ox-LDL via LDLR and LOX-1; LDL and Ox-LDL are then degraded into amino acids and free cholesterol by lysosomes. Free cholesterol can induce an increase in biliary cholesterol excretion in hepatocytes; furthermore, it can reduce cholesterol synthesis through feedback inhibition of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase. Hepatocytes can maintain stable lipid metabolism through other cholesterol metabolism pathways, such as the reverse cholesterol transport pathway. Note: The entire square region is a hepatocyte, and the nucleus (green sphere) is the centre of metabolic regulation. The nuclear transcription factor LXR/RXR located in the nucleus regulates the expression of the cholesterol transporters ABCG5 and ABCG8, which secrete cholesterol into the lumen of the small intestine (the lower right area in the figure) as bile acids. SREBP-2 (RNA helix-like icon in the upper right of the figure) transcribed into the cytoplasm through the nucleus regulates the dynamic equilibrium between LDLR and PCSK9. LDLR (green arc-shaped transmembrane receptor in the figure), located on the cell membrane surface, is responsible for the uptake and metabolism of circulating LDL (near the cell membrane and cytoplasmic molecules and organelles in the upper left of the figure), and the ability of LDLR to recycle to the cell membrane after binding LDL and internalizing into hepatocytes is closely related to the regulation of PCSK9 (the red icon in the upper right of the figure). HDL-C is taken up through SR-BI (light green receptor with corresponding green spherical HDL icon in the lower right of the figure) on the surface of hepatocytes. In the endoplasmic reticulum (green reticular membrane icon in the cytoplasm in the middle-upper portion of the figure), HMG-CoA reductase synthesizes cholesterol, of which some is packaged into VLDL and secreted into the blood and some is stored after ACAT esterification