Cholesterol: from feeding to gene regulation

Abstract

We present here a brief description of the path that cholesterol covers from its intestinal absorption to its effects exerted on gene regulation. In particular, the relationship between cholesterol and the protein complexes involved in the intricate gene regulation mechanism implicated in cholesterol homeostasis will be discussed. In addition, a new target role for the pharmacological interventions of one of these factors, the insulin-induced gene (Insig) protein, will be introduced.

Fig. 1

Cholesterol structure

Fig. 2

Cholesterol intestinal absorption is a multi-step process. Here, there is a simplified picture illustrating that intestinal cholesterol derives from diet, bile and epithelial cells recycling. Cholesterol enters the enterocyte though a newly identified sterol influx transporter located at the apical membrane of the cell, the Niemann-Pick C1-like 1 protein (NPC1L1). ATP binding cassette G5/G8 (ABCG5/G8) promotes the efflux of cholesterol from the enterocyte into intestinal lumen for excretion. The combined regulatory effects of NPC1L1 and ABCG5/G8 may play a critical role in modulating cholesterol amount that reach the lymph. Once cholesterol is in the enterocyte, a lot of processes intervene to produce chylomicrons. Among them the cholesterol esterification is probably the most important

Fig. 3

LDL pathway and cholesterol influence on Insig/SCAP/SREBP fate. a When cellular cholesterol levels are high or normal, sterol regulatory element binding protein (SREBP), SREBP cleavage activating protein (SCAP) and insulin-induced gene (Insig) form a macromolecular complex in the endoplasmic reticulum (ER). b, c Low levels of cholesterol in ER allow Insig to escape from the complex and permit to SCAP/SREBP to escort into Golgi apparatus. d In Golgi apparatus, SREBP is cleaved and mature SREBP is released into cytoplasm from where migrates into nucleus

Fig. 4

Genes regulated by SREBPs. SREBP-1a is a potent activator of all SREBP-responsive genes, including those that mediate the synthesis of cholesterol, fatty acids, and triglycerides. High-level transcriptional activation is dependent on exon 1a, which encodes a longer acidic transactivation segment than does the first exon of SREBP-1c. The roles of SREBP-1c and SREBP-2 are more restricted than that of SREBP-1a. SREBP-1c preferentially enhances transcription of genes required for fatty acid synthesis but not cholesterol synthesis. Like SREBP-1a, SREBP-2 has a long transcriptional activation domain, but it preferentially activates cholesterol synthesis. SREBP-1a and SREBP-2 are the predominant isoforms of SREBP in most cultured cell lines, whereas SREBP-1c and SREBP-2 predominate in the liver and most other intact tissues