Cholesterol metabolism: physiological regulation and diseases

Abstract

Cholesterol homeostasis is crucial for cellular and systemic function. The disorder of cholesterol metabolism not only accelerates the onset of cardiovascular disease (CVD) but is also the fundamental cause of other ailments. The regulation of cholesterol metabolism in the human is an extremely complex process. Due to the dynamic balance between cholesterol synthesis, intake, efflux and storage, cholesterol metabolism generally remains secure. Disruption of any of these links is likely to have adverse effects on the body. At present, increasing evidence suggests that abnormal cholesterol metabolism is closely related to various systemic diseases. However, the exact mechanism by which cholesterol metabolism contributes to disease pathogenesis remains unclear, and there are still unknown factors. In this review, we outline the metabolic process of cholesterol in the human body, especially reverse cholesterol transport (RCT). Then, we discuss separately the impact of abnormal cholesterol metabolism on common diseases and potential therapeutic targets for each disease, including CVD, tumors, neurological diseases, and immune system diseases. At the end of this review, we focus on the effect of cholesterol metabolism on eye diseases. In short, we hope to provide more new ideas for the pathogenesis and treatment of diseases from the perspective of cholesterol.

Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis

“…The Srebp1 and Srebp2 have a bHLH-Zip region and ∼45% amino acid homology. In both of these proteins, the N-terminal side translocates to the nucleus and exerts transcription factor activity, and Srebp2 activates genes mainly encoding cholesterol and LDL receptors ( Guo et al, 2024 ). Srebp2 is regulated by post-translational modifications and it has been reported that nSrebp2 is degraded by the ubiquitin-proteasome system as a contributing factor to loss of function.…”

“…Srebp2 is synthesized as a precursor and processed into a mature nuclear form (nSrebp2) in the Golgi apparatus before becoming a functional transcription factor. In the nucleus, nSrebp2 regulates the expression of many genes involved in cholesterol homeostasis ( Guo et al, 2024 ). Srebp2 activity has also been reported to be reduced in neurodegenerative diseases such as Alzheimer’s disease ( Mohamed et al, 2018 ; Tang et al, 2023 ), and Srebp2 has been reported to play an important role in the supply of cholesterol required for myelination ( Zhou et al, 2021 ).…”