Gene Number: 338

Location: 2p24.1

Key Functions: Cholesterol transport, lipid metabolism, LDL particle assembly, triglyceride export, cardiovascular regulation

APOB (apolipoprotein B) encodes the principal structural and functional protein component of low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL)—the main lipoprotein particles responsible for transporting cholesterol, triglycerides, and other lipids throughout the bloodstream. As such, APOB plays an indispensable role in lipid metabolism, cardiovascular health, and energy homeostasis.

There are two major isoforms of apolipoprotein B, produced through tissue-specific mRNA editing:

• ApoB-100, synthesized in the liver, is the full-length form responsible for the assembly and secretion of VLDL, which later converts to LDL in the plasma. ApoB-100 contains the binding domain necessary for interaction with the LDL receptor (LDLR), facilitating cholesterol uptake by peripheral tissues.

  
  

• ApoB-48, expressed in the intestine, is a truncated form that constitutes a key structural component of chylomicrons, the lipoproteins that transport dietary lipids from the gut to the bloodstream. ApoB-48 lacks the LDL receptor–binding domain and therefore functions solely in lipid absorption and delivery.

  
  

In hepatic metabolism, APOB operates as a scaffold protein around which triglycerides, cholesterol esters, and phospholipids assemble to form lipoprotein particles. The process is critically dependent on microsomal triglyceride transfer protein (MTP), which loads lipids onto nascent ApoB during its translation in the endoplasmic reticulum. Failure in this co-translational lipidation process leads to ApoB degradation via proteasomal pathways and impaired VLDL production, resulting in systemic lipid imbalances.

Genetic variations in APOB have profound effects on plasma lipid levels and cardiovascular risk.

• Loss-of-function (LOF) mutations in APOB reduce lipoprotein secretion and LDL formation, resulting in familial hypobetalipoproteinemia (FHBL)—a condition characterized by abnormally low LDL-C and total cholesterol levels, often protective against atherosclerosis. However, severe LOF variants can lead to hepatic steatosis due to impaired lipid export from the liver.

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• Conversely, missense or gain-of-function (GOF) variants, particularly those affecting the LDL receptor–binding domain (e.g., R3500Q and R3500W), cause familial defective apolipoprotein B-100 (FDB), a monogenic form of hypercholesterolemia. These mutations diminish ApoB’s affinity for LDL receptors, resulting in decreased hepatic LDL clearance and elevated plasma LDL-C, promoting atherosclerotic plaque formation and early-onset coronary artery disease (CAD).

  
  

Beyond lipid transport, ApoB-containing lipoproteins also influence vascular inflammation and endothelial function. Elevated ApoB concentrations correlate more strongly with atherogenic potential than total LDL-C levels, as ApoB provides a direct measure of the number of circulating atherogenic particles capable of infiltrating arterial walls. Once retained in the subendothelial space, these LDL particles undergo oxidative modification, triggering macrophage uptake via scavenger receptors, foam cell formation, and plaque development—key steps in atherogenesis.

From a therapeutic standpoint, APOB expression and function are indirectly modulated by statins and PCSK9 inhibitors, which enhance LDL receptor recycling and clearance of ApoB-containing lipoproteins. Novel therapies targeting ApoB synthesis directly—such as antisense oligonucleotides (e.g., mipomersen)—have demonstrated efficacy in lowering LDL-C in individuals with refractory familial hypercholesterolemia, although hepatic fat accumulation remains a limiting side effect.

At the molecular level, APOB is tightly regulated by nutritional status, insulin signaling, and intracellular lipid content. Insulin suppresses APOB transcription and promotes ApoB degradation, contributing to the postprandial reduction in VLDL secretion. Insulin resistance, by contrast, disrupts this feedback, leading to hypertriglyceridemia and the overproduction of small, dense LDL particles—both hallmarks of metabolic syndrome and type 2 diabetes.

In summary, APOB serves as the cornerstone of plasma lipoprotein architecture, orchestrating the transport and distribution of lipids throughout the body. Its precise regulation is essential for maintaining cholesterol homeostasis, vascular integrity, and metabolic balance. Genetic or functional disturbances in APOB translate directly into dyslipidemia and cardiovascular pathology, making it a pivotal biomarker and therapeutic target in cardiometabolic medicine.