What is local de novo (new) cholesterol synthesis?

Local De Novo Cholesterol Synthesis

Local de novo cholesterol synthesis refers to the process by which cells produce cholesterol internally from precursor molecules rather than acquiring it from circulating lipoproteins in the bloodstream. 1, 2

Biochemical Pathway and Regulation

• De novo cholesterol synthesis occurs primarily in the endoplasmic reticulum of cells, where acetate is converted to cholesterol through a complex multi-step pathway 1
• The liver is the primary site of cholesterol synthesis in the body, but many other tissues and cell types can synthesize cholesterol locally when needed 1
• VLDL cholesterol is either synthesized in the liver from acetate or delivered to the liver by lipoproteins, mainly chylomicron remnants 1
• ATP citrate lyase (ACL) is a key enzyme in this pathway, generating acetyl coenzyme A for de novo synthesis of fatty acids and cholesterol 1

Tissue-Specific Synthesis

• Brain cholesterol is primarily derived by de novo synthesis since the blood-brain barrier prevents the uptake of lipoprotein cholesterol from circulation 1, 3
• Local de novo cholesterol synthesis in the brain is essential for normal brain development and function, with defects leading to various neurological disorders 3
• Adipocytes (fat cells) have been shown to possess the machinery for de novo cholesterol synthesis, including the enzyme CYP11A1 which can produce pregnenolone from cholesterol 4
• Breast cancer cells often exhibit increased de novo cholesterol synthesis, which is associated with neoplastic transformation and tumor progression 5

Physiological Significance

• De novo cholesterol synthesis increases when dietary cholesterol intake is low or when cellular demand for cholesterol increases 1, 6
• When intestinal cholesterol absorption is blocked (e.g., with ezetimibe), de novo cholesterol synthesis increases by approximately 57% as a compensatory mechanism 6
• The rate of de novo synthesis is tightly regulated by feedback mechanisms involving cholesterol levels and cellular needs 1
• In pregnancy, altered de novo lipogenesis (including cholesterol synthesis) may be associated with gestational complications such as gestational diabetes mellitus 1

Clinical Implications

• Bempedoic acid, an inhibitor of ATP citrate lyase, reduces de novo cholesterol synthesis and is used as a third-line therapy for hyperlipidemia 1, 7
• Statins, the first-line therapy for hyperlipidemia, work by inhibiting HMG-CoA reductase, a rate-limiting enzyme in the de novo cholesterol synthesis pathway 7
• Local de novo cholesterol synthesis in tissues may continue even when plasma cholesterol levels are very low, which is important for maintaining essential cellular functions 1
• In certain genetic disorders like Smith-Lemli-Opitz syndrome, defects in cholesterol synthesis lead to developmental abnormalities and neurological problems 1, 3

Metabolic Interactions

• De novo cholesterol synthesis is part of a complex network of lipid metabolism that includes fatty acid synthesis, lipoprotein assembly, and steroid hormone production 1, 2
• In adipocytes, the oxysterol 27-hydroxycholesterol (27HC) is a major product of de novo cholesterol synthesis and may play a role in regulating adipocyte differentiation 4
• Increased de novo cholesterol synthesis can contribute to the formation of small, dense LDL particles, which are more atherogenic 1
• The process is energy-intensive, requiring significant ATP consumption, which makes it metabolically expensive for cells 2, 5