Liver X receptors in lipid signalling and membrane homeostasis

Abstract

Liver X receptors α and β (LXRα and LXRβ) are nuclear receptors with pivotal roles in the transcriptional control of lipid metabolism. Transcriptional activity of LXRs is induced in response to elevated cellular levels of cholesterol. LXRs bind to and regulate the expression of genes that encode proteins involved in cholesterol absorption, transport, efflux, excretion and conversion to bile acids. The coordinated, tissue-specific actions of the LXR pathway maintain systemic cholesterol homeostasis and regulate immune and inflammatory responses. LXRs also regulate fatty acid metabolism by controlling the lipogenic transcription factor sterol regulatory element-binding protein 1c and regulate genes that encode proteins involved in fatty acid elongation and desaturation. LXRs exert important effects on the metabolism of phospholipids, which, along with cholesterol, are major constituents of cellular membranes. LXR activation preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids by inducing transcription of the remodelling enzyme lysophosphatidylcholine acyltransferase 3. The ability of the LXR pathway to couple cellular sterol levels with the saturation of fatty acids in membrane phospholipids has implications for several physiological processes, including lipoprotein production, dietary lipid absorption and intestinal stem cell proliferation. Understanding how LXRs regulate membrane composition and function might provide new therapeutic insight into diseases associated with dysregulated lipid metabolism, including atherosclerosis, diabetes mellitus and cancer.

Fig. 1 |. LXRs are lipid-responsive transcription factors.

Liver X receptors (LXRs) and retinoid X receptors (RXRs) form heterodimers and bind to LXR response elements (LXREs) in the regulatory regions of their target genes. The target regions consist of variations of the repeated sequence AGGTCA, separated by four nucleotides (N). In the absence of ligands, the LXR–RXR complex binds co-repressors and suppresses gene expression. When LXRs are activated by oxysterols or synthetic ligands and/or RXR is activated by its ligands, such as 9-cis-retinoic acid, the co-repressors are replaced by co-activators, thereby activating the expression of target genes involved in lipid metabolism. ASC2, activating signal co-integrator 2; EP300, histone acetyltransferase p300; NCoR, nuclear receptor co-repressor; SMRT, silencing mediator of retinoic acid and thyroid hormone receptor.

Fig. 2 |. LXR signalling pathways in cholesterol and fatty acid metabolism.

Liver X receptor (LXR) activation modulates cholesterol and fatty acid metabolism in a tissue-specific manner. LXR targets are shown in red. In the liver, LXR agonism promotes the conversion of cholesterol into bile acids via cytochrome P450 7A1 (CYP7A1) and biliary cholesterol excretion through ATP-binding cassette subfamily G members 5 and 8 (ABCG5 and ABCG8, respectively). LXR inhibits cholesterol uptake in the liver and macrophages through inducing the expression of inducible degrader of the LDL receptor (IDOL) and the degradation of LDL receptor (LDLR). LXR activation suppresses cholesterol biosynthesis in liver by inducing the transcription of non-coding RNA LXR-induced sequence (Lexis) and E3 ubiquitin protein ligase RING finger protein 145 (RNF145). LXR activation promotes fatty acid biosynthesis by inducing the expression of sterol regulatory element-binding protein 1c (SREBP1c), carbohydrate-response element-binding protein (ChREBP) and their targets, fatty acid synthase (FASN) and stearoyl-coenzyme A desaturase 1 (SCD1). In peripheral cells such as macrophages, LXRs increase expression of ATP-binding cassette subfamily A member 1 (ABCA1), ABCG1 and ADP-ribosylation factor-like protein 7 (ARL7), thereby promoting cholesterol movement to the plasma membrane and cholesterol efflux to apolipoprotein A1 (ApoA1) or pre-β HDL. In the intestine, LXR activation increases HDL formation via basolateral ABCA1 and promotes cholesterol efflux and trans-intestinal cholesterol excretion through ABCG5 and ABCG8. LXR also inhibits cholesterol absorption by indirectly inhibiting Niemann–Pick C1-like protein 1 (NPC1L1). The dashed arrows indicate reduced cholesterol uptake.

Fig. 3 |. Roles of LXR-dependent phospholipid remodelling in liver.

a | The effects of liver X receptor (LXR) activation. LXR activation promotes the incorporation of polyunsaturated fatty acids into phospholipids through the induction of lysophosphatidylcholine acyltransferase 3 (LPCAT3) expression. Polyunsaturated phospholipids facilitate sterol regulatory element-binding protein 1c (SREBP1c) transport from the endoplasmic reticulum (ER) to the Golgi and its proteolytic cleavage, thereby promoting lipogenesis. LXR agonists and LPCAT3 activation also promote VLDL secretion. Increased abundance of polyunsaturated phospholipids creates a dynamic membrane environment that facilitates the transfer of triglyceride to nascent apolipoprotein B (ApoB)-containing lipoprotein particles, leading to the efficient lipidation of ApoB-containing lipoproteins. b | Consequences of LPCAT3 deficiency. Loss of LPCAT3 expression reduces the composition of polyunsaturated phospholipids in the ER membrane and impairs the translocation of SREBP1c from the ER to the Golgi and its proteolytic cleavage. SCAP, sterol regulatory element-binding protein cleavage-activating protein; SRE, sterol response element.

Fig. 4 |. LPCAT3 and phospholipid remodelling in lipid absorption and intestinal homeostasis.

a | Lysophosphatidylcholine acyltransferase 3 (LPCAT3) activity regulates lipid absorption in the small intestine. Loss of LPCAT3 in the intestine reduces polyunsaturated phospholipid content and membrane fluidity, resulting in impaired passive fatty acid transport into enterocytes and chylomicron production. When challenged with a triglyceride-rich diet, LPCAT3-deficient mice produce more gut hormones (glucagon-like peptide 1 (GLP1) or peptide YY (PYY)), leading to the inhibition of food intake. b | Loss of LPCAT3 increases membrane saturation and stimulates cholesterol biosynthesis, thereby driving the proliferation of intestinal stem cells and progenitor cells. Consequently, LPCAT3 deficiency and cholesterol biosynthesis enhance tumour formation in Apc^min/+ mice.