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Review
. 2022 Feb 15;205(4):388-396.
doi: 10.1164/rccm.202105-1197TR.

The Many Roles of Cholesterol in Sepsis: A Review

Daniel A Hofmaenner  1 , Anna Kleyman  1 , Adrian Press  2 , Michael Bauer  2 , Mervyn Singer  1
Affiliations
Review

The Many Roles of Cholesterol in Sepsis: A Review

Daniel A Hofmaenner et al. Am J Respir Crit Care Med. .

Abstract

The biological functions of cholesterol are diverse, ranging from cell membrane integrity, cell membrane signaling, and immunity to the synthesis of steroid and sex hormones, vitamin D, bile acids, and oxysterols. Multiple studies have demonstrated hypocholesterolemia in sepsis, the degree of which is an excellent prognosticator of poor outcomes. However, the clinical significance of hypocholesterolemia has been largely unrecognized. We undertook a detailed review of the biological roles of cholesterol, the impact of sepsis, its reliability as a prognosticator in sepsis, and the potential utility of cholesterol as a treatment. Sepsis affects cholesterol synthesis, transport, and metabolism. This likely impacts its biological functions, including immunity, hormone and vitamin production, and cell membrane receptor sensitivity. Early preclinical studies show promise for cholesterol as a pleiotropic therapeutic agent. Hypocholesterolemia is a frequent condition in sepsis and an important early prognosticator. Low plasma concentrations are associated with wider changes in cholesterol metabolism and its functional roles, and these appear to play a significant role in sepsis pathophysiology. The therapeutic impact of cholesterol elevation warrants further investigation.

Keywords: cholesterol; hypocholesterolemia; lipid metabolism; sepsis.

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Figures

Figure 1.
Figure 1.
Cholesterol structure and location within cell membranes. GPI = glycosylphosphatidylinositol.
Figure 2.
Figure 2.
Cholesterol synthesis and metabolism pathways and impact of sepsis. *Plasma concentrations may be normal or raised for adrenocorticoid hormones and bile acids, but this may relate to decreased metabolism and/or excretion rather than to increased production. Cortisol concentrations frequently fail to augment with exogenous ACTH (adrenocorticotropic hormone) stimulation. The question mark represents uncertain effect. ABC1 = ATP-binding cassette transporter 1; AMPK = AMP-activated protein kinase; ApoA1 = apolipoprotein A1; HDL = high-density lipoprotein; HMG-CoA = hydroxymethylglutaryl–coenzyme A; INSIG = insulin-induced gene 1 protein; LCAT = lecithin–cholesterol acyltransferase; LDL = low-density lipoprotein; SCAP = SREBP cleavage–activating protein; SIRT-1 = sirtuin 1; SREBP = sterol regulatory element–binding protein; VLDL = very-low-density lipoprotein.
Figure 3.
Figure 3.
Functional roles of cholesterol.
Figure 4.
Figure 4.
Impact of sepsis on cholesterol transport. ABC = ATP-binding cassette transporter; CETP = cholesteryl ester transfer protein; HDL = high-density lipoprotein; LCAT = lecithin–cholesterol acyltransferase; LDL = low-density lipoprotein; LDL-R = LDL receptor; PCSK9 = proprotein convertase subtilisin kexin 9; SR-BI = scavenger receptor B type 1; VLDL = very-low-density lipoprotein.
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