Revisiting Human Cholesterol Synthesis and Absorption: The Reciprocity Paradigm and its Key Regulators

Abstract

Hypercholesterolemia is a major risk factor for cardiovascular disease. Cholesterol homeostasis in the body is governed by the interplay between absorption, synthesis, and excretion or conversion of cholesterol into bile acids. A reciprocal relationship between cholesterol synthesis and absorption is known to regulate circulating cholesterol in response to dietary or therapeutic interventions. However, the degree to which these factors affect synthesis and absorption and the extent to which one vector shifts in response to the other are not thoroughly understood. Also, huge inter-individual variability exists in the manner in which the two systems act in response to any cholesterol-lowering treatment. Various factors are known to account for this variability and in light of recent experimental advances new players such as gene-gene interactions, gene-environmental effects, and gut microbiome hold immense potential in offering an explanation to the complex traits of inter-individual variability in human cholesterol metabolism. In this context, the objective of the present review is to provide an overview on cholesterol metabolism and discuss the role of potential factors such as genetics, epigenetics, epistasis, and gut microbiome, as well as other regulators in modulating cholesterol metabolism, especially emphasizing the reciprocal relationship between cholesterol synthesis and absorption. Furthermore, an evaluation of the implications of this push-pull mechanism on cholesterol-lowering strategies is presented.

The Role of Lipid Biomarkers in Major Depression

“…Instead, cholesterol is predominantly synthesised in human cells by a complex synthetic pathway [22]. This is a multi-step process controlled by a series of enzymes.…”

Physiological and molecular responses to bariatric surgery: markers or mechanisms underlying T2DM resolution?

“…). All bile acids can be conjugated to glycine or taurine within the liver to form bile salts . Thus, the term “bile acids” represents a pool of different molecules with potentially diverse biological activity.…”

“…All bile acids can be conjugated to glycine or taurine within the liver to form bile salts. 85 Thus, the term "bile acids" represents a pool of different molecules with potentially diverse biological activity. Although the traditionally known function of bile acids is lipid emulsification, they are also known to act as signaling molecules.…”

A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia

“…In patients with compound heterozygous or homozygous mutations in the LDLR (referred to collectively as hoFH), LDL-C levels reach >500 mg/dL which leads to the formation of xanthomas, severe cardiovascular disease, and early death (Rader et al, 2003). Importantly, although the LDLR is broadly expressed, the disease can be cured by liver transplantation indicating that the hepatic LDLR is the primary regulator of serum LDL-C levels (Alphonse and Jones, 2016). Most drugs that lower serum LDL-C work on the liver through upregulation of LDLR transcription (statins) or stability of the LDLR protein (Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors) (Nissen et al, 2016; Thompson et al, 2003).…”