Introduction
The liver is a central metabolic organ responsible for maintaining systemic lipid homeostasis through tightly regulated processes such as fatty acid uptake, oxidation, and the assembly and secretion of very low-density lipoproteins (VLDLs). These pathways allow the liver to detoxify excess circulating free fatty acids and redistribute lipids to peripheral tissues for energy utilization. Disruption of these mechanisms contributes to hepatic lipid accumulation and the development of metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD). Given the close association between hepatic lipid dysregulation, cardiovascular disease, and metabolic disorders, understanding liver lipid metabolism remains a major focus of biomedical research.
Hepatic Fatty Acid Uptake and Intracellular Trafficking
Hepatic fatty acid uptake occurs through both passive diffusion and transporter-mediated mechanisms involving proteins such as CD36 and fatty acid transport proteins (FATPs). Once inside hepatocytes, fatty acids are esterified, oxidized, or incorporated into lipoproteins. Intracellular trafficking of fatty acids toward mitochondria, peroxisomes, or the endoplasmic reticulum is tightly regulated to prevent lipotoxicity. Dysregulation at this stage can shift lipid flux toward storage rather than oxidation, promoting hepatic steatosis and metabolic stress, making this process a critical area for mechanistic and translational research.
Fatty Acid Oxidation and Hepatic Energy Homeostasis
Fatty acid oxidation is essential for maintaining hepatic energy balance and preventing lipid overload. Mitochondrial β-oxidation serves as the primary pathway for fatty acid catabolism, while peroxisomal oxidation handles very-long-chain fatty acids. Impairment in these oxidative pathways leads to lipid accumulation, mitochondrial dysfunction, oxidative stress, and inflammation—hallmarks of MASLD progression. Current research focuses on transcriptional regulators such as PPARα and AMPK, which coordinate fatty acid oxidation and represent potential therapeutic targets.
VLDL Biogenesis: Molecular Assembly and Lipidation
VLDL biogenesis is a multistep process initiated in the endoplasmic reticulum, where apolipoprotein B100 (ApoB100) is lipidated by microsomal triglyceride transfer protein (MTP). This process ensures efficient packaging of triglycerides and cholesterol into nascent lipoprotein particles. Defects in VLDL assembly can result in intracellular triglyceride accumulation, exacerbating hepatic steatosis. Despite its importance, the precise regulation of ApoB stability, lipid availability, and ER quality control during VLDL formation remains incompletely understood.
Regulation of VLDL Secretion and Systemic Lipid Distribution
Once assembled, VLDLs are secreted into the circulation to deliver triglycerides to peripheral tissues. This secretion process plays a protective role by exporting excess hepatic lipids; however, excessive VLDL output contributes to hypertriglyceridemia and atherosclerosis. Hormonal signals, nutrient availability, and insulin resistance strongly influence VLDL secretion rates. Ongoing research aims to clarify how altered hepatic insulin signaling selectively enhances VLDL secretion while failing to suppress lipid synthesis in metabolic disease states.
Clinical Implications and Future Research Directions
Dysregulation of fatty acid oxidation and VLDL metabolism links MASLD to systemic metabolic disorders, including type 2 diabetes and cardiovascular disease. Given that atherosclerosis remains the leading cause of global mortality, hepatic lipid handling has emerged as a critical determinant of cardiometabolic risk. Future research must integrate molecular biology, omics technologies, and clinical studies to unravel unresolved mechanisms governing hepatic lipid balance. Advancing this knowledge is essential for developing targeted therapies to prevent liver disease progression and reduce cardiovascular morbidity.
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