Metabolic Dysfunction-Associated Steatotic Liver Disease: From a Very Low-Density Lipoprotein Perspective

Figure 1. Plot of triglyceride accumulation in the liver. The metabolic process of FFA in the liver and its relationship with dietary fat and NEFAs. FFA is the central substance of fatty acid metabolism, which is derived from the following: dietary intake; de novo fat synthesis; and non-esterified fatty acids. The destination is through the liver mitochondria oxidation, converting to triglycerides, and through the VLDL transport in the liver.

Figure 2. The relationship between the pathogenesis of MASLD and VLDL. VLDL (very low-density lipoprotein); FFA (free fatty acid); IR (insulin resistance); SREBP-1C (Sterol Regulatory Element Binding Protein-1C); HDL (high-density lipoprotein); TGs (triglycerides); SCFAs (short-chain fatty acids); CETP (Cholesteryl Ester Transfer Protein); FXR (Farnesoid X Receptor); TGR5 (TGR5 Bile Acid Receptor); JNK (c-Jun N-terminal kinase); IKKβ (IκB Kinase β); Nrf2 (nuclear factor E2-related factor 2); IRE1α-XBR1 (Inositol-Requiring Enzyme 1 alpha–X-Box Binding Protein 1). Note: ↑ indicates an increase in content, and ↓ indicates a decrease in content.

Figure 3. Structure of VLDL. The components of VLDL mainly include TG, cholesterol, cholesterol esters, phospholipids, and proteins. The protein part includes apolipoprotein ApoE, ApoC-I, ApoC-II, ApoC-III, ApoA-I, ApoA-II, ApoA-IV, and ApoA-V.

Figure 4. This is a simple diagram of VLDL assembly, secretion, and transport out of the cell. The biosynthesis of VLDL begins in the endoplasmic reticulum (ER), the primary site for protein synthesis and lipid metabolism. Newly synthesized apolipoprotein B-100 (ApoB-100) must undergo a lipidation process mediated by microsomal triglyceride transfer protein (MTP). This process involves the binding of triglycerides (TGs) and phospholipids (PLs) to ApoB-100, forming the precursor of VLDL. The VLDL precursor then binds additional triglycerides (TGs) to form mature VLDL particles. Mature VLDL particles are transported from the endoplasmic reticulum (ER) to the Golgi apparatus via vesicle transport. In the Golgi apparatus, VLDL particles undergo significant modifications, including glycosylation and further lipidation, which ultimately complete their maturation. After these modifications, the mature VLDL particles are packaged into transport vesicles and secreted into the bloodstream via exocytosis.

Figure 5. The relationship between steatosis and VLDL secretion. MTTP, ApoB, ApoE, VLDL-R, and phospholipids damaged or missing will affect the synthesis or secretion of VLDL; similarly, insulin resistance, NEFA, or endoplasmic reticulum stress activation or overload will also affect VLDL, leading to lipid accumulation. Note: ↑ indicates an increase in content, and ↓ indicates a decrease in content.