An overview of the cholesterol metabolism and its proinflammatory role in the development of MASLD - PubMed (original) (raw)

Review

An overview of the cholesterol metabolism and its proinflammatory role in the development of MASLD

Linqiang Zhang et al. Hepatol Commun. 2024.

Abstract

Cholesterol is an essential lipid molecule in mammalian cells. It is not only involved in the formation of cell membranes but also serves as a raw material for the synthesis of bile acids, vitamin D, and steroid hormones. Additionally, it acts as a covalent modifier of proteins and plays a crucial role in numerous life processes. Generally, the metabolic processes of cholesterol absorption, synthesis, conversion, and efflux are strictly regulated. Excessive accumulation of cholesterol in the body is a risk factor for metabolic diseases such as cardiovascular disease, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). In this review, we first provide an overview of the discovery of cholesterol and the fundamental process of cholesterol metabolism. We then summarize the relationship between dietary cholesterol intake and the risk of developing MASLD, and also the animal models of MASLD specifically established with a cholesterol-containing diet. In the end, the role of cholesterol-induced inflammation in the initiation and development of MASLD is discussed.

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Conflict of interest statement

The authors have no conflicts to report.

Figures

FIGURE 1

Timeline of important events and promising discoveries in cholesterol research. (A) Timeline of advances in the research history of cholesterol. (B) The number of publications published each year using the following search query in a January 2024 search of PubMed: “cholesterol” or “cholesterol and fatty liver.” (C) Nobel Prizes in the research field of cholesterol and lipids. Abbreviations: CAD, coronary artery disease; FDA, Food and Drug Administration; FH, familial hypercholesterolemia; HMG, 3-hydroxy-3-methylglutaryl-CoA; SREBP, sterol regulatory element-binding protein.

FIGURE 2

Cholesterol homeostasis in human and mouse. The body pool of cholesterol in adult male human (without parentheses) and adult male mouse (with parentheses) are maintained by a dynamic balance between cholesterol input and output. Abbreviation: BW, body weight.

FIGURE 3

An overview of cholesterol biosynthesis pathway. The dark colors represent a schematic representation of the three stages of cholesterol biosynthesis. Abbreviations: FDPS, farnesyl diphosphate synthase; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; MDD, mevalonate diphosphate decarboxylase; PMK, phosphomevalonate kinase; MK, mevalonate kinase; OSC, oxidosqualene cyclase; SQS, squalene synthase.

FIGURE 4

Cholesterol and lipoprotein metabolism. Abbreviations: ABCA1, ATP-binding cassette transporter A1; ABCG5/G8, ATP-binding cassette transporter G5/G8; ACAT1/2, acetyl-coA acetyltransferase ½; ASBT, apical sodium-dependent bile acid transporter; BA, bile acid; BSEP, bile salt export pump; CE, cholesterol ester; CM, chylomicrons; CMr, chylomicron remnants; CYP27A1, cytochrome P450 27A1; CYP7A1, cytochrome P450 7A1; FC, free cholesterol; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; LD, lipid droplets; LDLR, Low density lipoprotein receptor; LPL, lipoprotein lipase; LRP1, low-density lipoprotein receptor-related protein-1; MTTP, microsomal triglyceride transfer protein; NPC1L1, Niemann-pick C1 Like 1; SM, squalene monooxygenase; SR-B1, scavenger receptor B1.

FIGURE 5

Animal models of NAFLD induced by cholesterol-containing diet. The inner circle indicates the different animal models, where green indicates rodent models and blue indicates nonrodent models. The outer circle shows the characteristics of the relevant animal model. Abbreviations: MASLD, metabolic dysfunction–associated steatotic liver disease.

FIGURE 6

Role of cholesterol crystal in the development of MASH. Abbreviations: aHSC, activated-hepatic stellate cell; EC, endothelial cell; hCLS, hepatic crown-like structures; NLRP3, NOD-, LRR-, and pyrin domain-containing 3.

FIGURE 7

Overview of the different cell types and characteristics of CD4+ T cells in the pathophysiology of MASLD. Abbreviations: AHR, aryl hydrocarbon receptor; CCR, C-C motif chemokine receptor; CTLA4, cytotoxic T-lymphocyte-associated protein 4; CXCR, C-X-C motif chemokine receptor; FoxP3, forkhead box P3; GATA-3, GATA binding protein 3; IFN-γ, interferon-gamma; RA, retinoic acid; ROR-γt, retinoic acid-related orphan receptor γ-t; STAT, signal transducer and activator of transcription; T-bet, T-box expressed in T cells; Th1, T helper 1; Th17, T helper 17; Th2, T helper 2; Th22 T helper 22; Treg, regulatory T cell.

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An overview of the cholesterol metabolism and its proinflammatory role in the development of MASLD - PubMed (original) (raw)