LDL Receptor Deficiency Research Articles

Plasma PCSK9 in Nephrotic Syndrome and in Peritoneal Dialysis: A Cross-sectional Study

Serum total and low-density lipoprotein (LDL) cholesterol levels are elevated in patients with nephrotic syndrome and those with kidney failure treated by peritoneal dialysis (PD), who are characterized by heavy losses of protein in urine and peritoneal dialysate, respectively. Hypercholesterolemia in nephrotic syndrome is associated with and largely due to acquired LDL receptor (LDLR) deficiency. Because PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes degradation of LDLR, we tested the hypothesis that elevation of LDL cholesterol levels in patients with nephrotic syndrome and PD patients may be due to increased PCSK9 levels. Cross-sectional study. Patients with nephrotic syndrome or treated by PD or hemodialysis and age- and sex-matched healthy Korean individuals (n=15 in each group). Group and serum total and LDL cholesterol levels. Plasma PCSK9 concentration. Concentrations of fasting serum PCSK9, lipids, and albumin, and urine protein excretion. Mean serum total and LDL cholesterol levels in patients with nephrotic syndrome (317.9±104.2 [SD] and 205.9±91.1mg/dL) and PD patients (200.0±27.6 and 126.7±18.5mg/dL) were significantly (P<0.05) higher than in hemodialysis patients (140.9±22.9 and 79.1±19.5mg/dL) and the control group(166.5±26.5 and 95.9±25.2mg/dL). This was associated with significantly (P<0.05) higher plasmaPCSK9 levels in patients with nephrotic syndrome (15.13±4.99ng/mL) and PD patients (13.30±1.40ng/mL) than in the control (9.19±0.60ng/mL) and hemodialysis (7.30±0.50ng/mL) groups. Plasma PCSK9 level was directly related to total and LDL cholesterol concentrations in the study population (r=0.559 [P<0.001] and r=0.497 [P<0.001], respectively). Small number of participants may limit generalizability. Nephrotic syndrome and PD are associated with higher plasma PCSK9 concentration, which can contribute to elevation of LDL levels by promoting LDLR deficiency.

Role of PCSK9 and IDOL in the pathogenesis of acquired LDL receptor deficiency and hypercholesterolemia in nephrotic syndrome

Nephrotic syndrome (NS) leads to elevation of serum total and LDL cholesterol. This is largely due to impaired LDL clearance, which is caused by hepatic LDL receptor (LDLR) deficiency despite normal LDLR mRNA expression, pointing to a post-transcriptional process. The mechanism(s) by which NS causes LDLR deficiency is not known. By promoting degradation of LDLR, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and inducible degrader of the LDL receptor (IDOL) play a major role in post-translational regulation of LDLR. We, therefore, tested the hypothesis that LDLR deficiency despite its normal gene expression in NS may be due to upregulation of hepatic PCSK9 and IDOL. LDLR, IDOL and PCSK9 expressions and nuclear translocation of liver X receptor (LXR) that regulates IDOL expression were determined in the liver of rats with puromycin-induced NS and control (CTL) rats. Compared with the CTLs, the NS rats showed marked elevation of serum total and LDL cholesterol and a significant reduction in hepatic LDLR protein expression. This was accompanied by marked upregulation of hepatic PCSK9 and IDOL expressions and heightened LXR activation. LDLR deficiency, hypercholesterolemia and elevated plasma LDL in NS are associated with upregulation of PCSK9 and IDOL. Interventions targeting these pathways may be effective in the management of hypercholesterolemia and the associated cardiovascular and other complications of NS.

Relaxation of porcine retinal arterioles exposed to hypercholesterolemia in vivo is modified by hepatic LDL-receptor deficiency and diabetes mellitus

Metabolic disturbances in diabetes mellitus include changes in the type and concentration of lipids in the blood plasma which may contribute to the development of diabetic retinopathy. This disease is characterized by changes in retinal blood flow secondary to changes in the tone of retinal arterioles which is regulated by compounds such as adenosine, adenosine triphosphate (ATP), the glutamate agonist N-methyl-d-aspartate (NMDA) and prostaglandin E2 (PGE2). However, the relation between increased plasma low density lipoprotein (LDL) and tone regulation in retinal resistance vessels has not been studied in detail. Twelve male and nine female Yucatan minipigs overexpressing a gain-of-function mutant (D374Y) of the human gene PCSK9 that blocks LDL transport into the liver and twelve wild-type males were studied. The animals were fed a cholesterol rich diet from the age of 60 days, followed by induction of diabetes mellitus in twelve of the transgenic animals. The animals were sacrificed at a mean age of 51 weeks (range 26–60 weeks), followed by inspection and histological examination of retinal vessels, and examination of the changes in vascular tone induced by adenosine, ATP, NMDA and PGE2. In the transgenic pigs without diabetes mellitus ATP-induced relaxation was reduced in isolated arterioles, and a whitish infiltration in an arteriole was observed in 4/8 (50%) of the animals, whereas these changes were not found in the other groups. Histological examination of one of the infiltrations showed staining with Oil Red O representing foamy cells sub-endothelially in the vascular wall indicating atheromatosis. Adenosine, ATP and PGE2 induced a significant concentration-dependent relaxation of retinal arterioles in all groups. The presence of perivascular retinal tissue had no effect on the relaxing effect of adenosine, but increased the relaxing effect of ATP and PGE2 in the two transgenic animal groups, whereas NMDA had no significant effect on vascular tone in any of the groups. Relaxation of porcine retinal arterioles exposed to hypercholesterolemia in vivo is modified by hepatic LDL-receptor deficiency and diabetes mellitus. This suggests that transgenic animal models are suitable for studying the influence of systemic diseases on retinal vascular function.

FRI0044 Cholesterol accumulation by low density lipoprotein receptor deficiency or a cholesterol-rich diet enhances osteophyte formation during experimental osteoarthritis by activating transforming growth factor-beta

BackgroundSynovial macrophages have previously shown to play a significant role in the etiopathology of experimental collagenase-induced osteoarthritis (OA)1. In addition to production of the pro-inflammatory protein S100A8/9 in early OA2,...

OP0090 LDL receptor deficiency results in osteophyte formation during experimental osteoarthritis which is increased under high cholesterol conditions

BackgroundSynovial macrophages have previously shown to be involved in joint destruction during experimental collagenase-induced osteoarthritis (OA). The low density lipoprotein (LDL) receptor expressed by synovial macrophages is involved in transport...

PPAR Agonist-Induced Reduction of Mcp1 in Atherosclerotic Plaques of Obese, Insulin-Resistant Mice Depends on Adiponectin-Induced Irak3 Expression

Synthetic peroxisome proliferator-activated receptor (PPAR) agonists are used to treat dyslipidemia and insulin resistance. In this study, we examined molecular mechanisms that explain differential effects of a PPARα agonist (fenofibrate) and a PPARγ agonist (rosiglitazone) on macrophages during obesity-induced atherogenesis. Twelve-week-old mice with combined leptin and LDL-receptor deficiency (DKO) were treated with fenofibrate, rosiglitazone or placebo for 12 weeks. Only rosiglitazone improved adipocyte function, restored insulin sensitivity, and inhibited atherosclerosis by decreasing lipid-loaded macrophages. In addition, it increased interleukin-1 receptor-associated kinase-3 (Irak3) and decreased monocyte chemoattractant protein-1 (Mcp1) expressions, indicative of a switch from M1 to M2 macrophages. The differences between fenofibrate and rosiglitazone were independent of Pparγ expression. In bone marrow-derived macrophages (BMDM), we identified the rosiglitazone-associated increase in adiponectin as cause of the increase in Irak3. Interestingly, the deletion of Irak3 in BMDM (IRAK3−/− BMDM) resulted in activation of the canonical NFκB signaling pathway and increased Mcp1 protein secretion. Rosiglitazone could not decrease the elevated Mcp1 secretion in IRAK3−/− BMDM directly and fenofibrate even increased the secretion, possibly due to increased mitochondrial reactive oxygen species production. Furthermore, aortic extracts of high-fat insulin-resistant LDL-receptor deficient mice, with lower adiponectin and Irak3 and higher Mcp1, showed accelerated atherosclerosis. In aggregate, our results emphasize an interaction between PPAR agonist-mediated increase in adiponectin and macrophage-associated Irak3 in the protection against atherosclerosis by PPAR agonists.

High serum-cholesterol levels by either low density lipoprotein receptor deficiency or a cholesterol-rich diet results in synovial activation and osteophyte formation during experimental osteoarthritis

High serum-cholesterol levels by either low density lipoprotein receptor deficiency or a cholesterol-rich diet results in synovial activation and osteophyte formation during experimental osteoarthritis

The transient receptor potential vanilloid 4 ion channel regulates the biosynthetic response of chondrocytes to dynamic loading

The transient receptor potential vanilloid 4 ion channel regulates the biosynthetic response of chondrocytes to dynamic loading

Angiotensin-converting enzyme inhibition and food restriction restore delayed preconditioning in diabetic mice

BackgroundClassical and delayed preconditioning are powerful endogenous protection mechanisms against ischemia-reperfusion damage. However, it is still uncertain whether delayed preconditioning can effectively salvage myocardium in patients with co-morbidities, such as diabetes and the metabolic syndrome. We investigated delayed preconditioning in mice models of type II diabetes and the metabolic syndrome and investigated interventions to optimize the preconditioning potential.MethodsHypoxic preconditioning was induced in C57Bl6-mice (WT), leptin deficient ob/ob (model for type II diabetes) and double knock-out (DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome). Twenty-four hours later, 30 min of regional ischemia was followed by 60 min reperfusion. Left ventricular contractility and infarct size were studied. The effect of 12 weeks food restriction or angiotensin-converting enzyme inhibition (ACE-I) on this was investigated. Differences between groups were analyzed for statistical significance by student’s t-test or one-way ANOVA followed by a Fisher’s LSD post hoc test. Factorial ANOVA was used to determine the interaction term between preconditioning and treatments, followed by a Fisher’s LSD post hoc test. Two-way ANOVA was used to determine the relationship between infarct size and contractility (PRSW). A value of p<0.05 was considered significant.ResultsLeft ventricular contractility is reduced in ob/ob compared with WT and even further reduced in DKO. ACE-I improved contractility in ob/ob and DKO mice. After ischemia/reperfusion without preconditioning, infarct size was larger in DKO and ob/ob versus WT. Hypoxic preconditioning induced a strong protection in WT and a partial protection in ob/ob mice. The preconditioning potential was lost in DKO. Twelve weeks of food restriction or ACE-I restored the preconditioning potential in DKO and improved it in ob/ob.ConclusionDelayed preconditioning is restored by food restriction and ACE-I in case of type II diabetes and the metabolic syndrome.

Cholesterol accumulation caused by low density lipoprotein receptor deficiency or a cholesterol-rich diet results in ectopic bone formation during experimental osteoarthritis

IntroductionOsteoarthritis (OA) is associated with the metabolic syndrome, however the underlying mechanisms remain unclear. We investigated whether low density lipoprotein (LDL) accumulation leads to increased LDL uptake by synovial macrophages and affects synovial activation, cartilage destruction and enthesophyte/osteophyte formation during experimental OA in mice.MethodsLDL receptor deficient (LDLr−/−) mice and wild type (WT) controls received a cholesterol-rich or control diet for 120 days. Experimental OA was induced by intra-articular injection of collagenase twelve weeks after start of the diet. OA knee joints and synovial wash-outs were analyzed for OA-related changes. Murine bone marrow derived macrophages were stimulated with oxidized LDL (oxLDL), whereupon growth factor presence and gene expression were analyzed.ResultsA cholesterol-rich diet increased apolipoprotein B (ApoB) accumulation in synovial macrophages. Although increased LDL levels did not enhance thickening of the synovial lining, S100A8 expression within macrophages was increased in WT mice after receiving a cholesterol-rich diet, reflecting an elevated activation status. Both a cholesterol-rich diet and LDLr deficiency had no effect on cartilage damage; in contrast, ectopic bone formation was increased within joint ligaments (fold increase 6.7 and 6.1, respectively). Moreover, increased osteophyte size was found at the margins of the tibial plateau (4.4 fold increase after a cholesterol-rich diet and 5.3 fold increase in LDLr−/− mice). Synovial wash-outs of LDLr−/− mice and supernatants of macrophages stimulated with oxLDL led to increased transforming growth factor-beta (TGF-β) signaling compared to controls.ConclusionsLDL accumulation within synovial lining cells leads to increased activation of synovium and osteophyte formation in experimental OA. OxLDL uptake by macrophages activates growth factors of the TGF-superfamily.

Changing the Conversation Regarding Pediatric Cholesterol Screening

Changing the Conversation Regarding Pediatric Cholesterol Screening

Abstract 9566: LRP1 Deficiency Promotes Smooth Muscle Cell Apoptosis in Atherosclerotic Plaques via PDGF Receptor Mediated Downregulation of Bcl-2

Apoptosis of smooth muscle cells (SMCs) promotes instability of atherosclerotic plaques. Apoptosis is believed to be suppressed by growth factor dependent activation of PI 3-kinase (PI3K). We investigated the effect of LRP1 knockout driven elevated platelet-derived growth factor beta receptor (PDGFR) signaling on SMC apoptosis in atherosclerotic plaques. We quantified apoptotic TUNEL-positive SMCs in lesions from 12 months old LDLR-/-/smLRP1-/- double knockout mice. LDLR (low-density lipoprotein receptor) deficiency accelerates atherosclerosis in mice. LDLR-/-/smLRP1-/- increased the percentage of TUNEL-positive cells compared to LDLR-/-/smLRP1+/+ controls (3.6±0.7% vs. 0.7±0.3%,respectively, P &lt; 0.05, n = 6). Mutation of the PI3K binding site in the PDGFR in LDLR-/-/smLRP1-/--F2/F2 mice suppressed SMC apoptosis (2.4%±0.3%, P &lt; 0.05, n = 6) suggesting that the PDGFR exerts proapoptotic effects via PI3K. In vitro studies (Cell Death Detection ELISA) revealed that chronic stimulation of SMCs with PDGF-BB (96 h) led to 3.1±0.4-fold increased apoptosis (n=3, P&lt;0.05). To characterize proapoptotic PDGFR driven signaling pathways we analysed PDGFR mutants in which the binding sites for different signaling molecules were deleted. Lack of PI3K binding completely abolished the proapoptotic effect, whereas a mutant which only binds PI3K was able to induce apoptosis like the WT receptor. Further analysis of PDGFR mutants revealed that activation of PI3K led to induction of c-Myc and decreased expression of antiapoptotic Bcl-2 as assessed by RT-PCR and Westernblotting. siRNA mediated knockdown of c-Myc prevented both, Bcl-2 downregulation and PDGF induced apoptosis. Consistently, immunohistochemical analysis of atherosclerotic plaques from LDLR-/-/smLRP1-/- and LDLR-/-/smLRP1-/--F2/F2 mice revealed that PDGFR dependent activation of PI3K impairs the expression of antiapoptotic Bcl-2. In conclusion, our study identified a new PDGFR driven proapoptotic signaling pathway in SMCs. Chronically elevated PDGFR/PI3K signaling downregulates Bcl-2 via induction of c-Myc. This has direct implications in atherogenesis, as PDGF promotes cell death in atherosclerotic plaques, which can ultimately lead to plaque instability and rupture.

Adeno-Associated Virus Serotype 8 Gene Therapy Leads to Significant Lowering of Plasma Cholesterol Levels in Humanized Mouse Models of Homozygous and Heterozygous Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is a life-threatening genetic disease caused by mutations in the gene encoding low-density lipoprotein receptor (LDLR). As a bridge to clinical trials, we generated a "humanized" mouse model lacking LDLR and apolipoprotein B (ApoB) mRNA editing catalytic polypeptide-1 (APOBEC-1) expression and expressing a human ApoB100 transgene in order to permit more authentic simulation of in vivo interactions between the clinical transgene product, human LDLR (hLDLR), and its endogenous ligand, human ApoB100. On a chow diet, the humanized LDLR-deficient mice have substantial hypercholesterolemia and a lipoprotein phenotype more closely resembling human homozygous FH (hoFH) than in previous mouse models of FH. On injection of an adeno-associated virus serotype 8 (AAV8) vector encoding the human LDLR cDNA, significant correction of hypercholesterolemia was realized at doses as low as 1.5 × 10(11) genome copies (GC)/kg. Given that some patients with heterozygous FH (heFH) cannot be adequately treated with current therapy, we then extended our studies to similarly "humanized" mice that were heterozygous for LDLR deficiency, and that have a lipoprotein phenotype resembling heterozygous FH. Injection of AAV8-hLDLR brought about significant reduction in total and LDL cholesterol at doses as low as 5 × 10(11) GC/kg. Collectively, these data demonstrate the safety and efficacy of the liver-specific AAV8-hLDLR vector in the treatment of humanized mice modeling both hoFH and heFH.

The plasma concentration of HDL-associated apoM is influenced by LDL receptor-mediated clearance of apoB-containing particles

ApoM is mainly associated with HDL. Nevertheless, we have consistently observed positive correlations of apoM with plasma LDL cholesterol in humans. Moreover, LDL receptor deficiency is associated with increased plasma apoM in mice. Here, we tested the idea that plasma apoM concentrations are affected by the rate of LDL receptor-mediated clearance of apoB-containing particles. We measured apoM in humans each carrying one of three different LDL receptor mutations (n = 9) or the apoB3500 mutation (n = 12). These carriers had increased plasma apoM (1.34 ± 0.13 µM, P = 0.003, and 1.23 ± 0.10 µM, P = 0.02, respectively) as compared with noncarriers (0.93 ± 0.04 µM). When we injected human apoM-containing HDL into Wt (n = 6) or LDL receptor-deficient mice (n = 6), the removal of HDL-associated human apoM was delayed in the LDL receptor-deficient mice. After 2 h, 54 ± 5% versus 90 ± 8% (P < 0.005) of the initial amounts of human apoM remained in the plasma of Wt and LDL receptor-deficient mice, respectively. Finally, we compared the turnover of radio-iodinated LDL and plasma apoM concentrations in 45 normocholesterolemic humans. There was a negative correlation between plasma apoM and the fractional catabolic rate of LDL (r = -0.38, P = 0.009). These data suggest that the plasma clearance of apoM, despite apoM primarily being associated with HDL, is influenced by LDL receptor-mediated clearance of apoB-containing particles.

Angiotensin-converting enzyme inhibition and food restriction in diabetic mice do not correct the increased sensitivity for ischemia-reperfusion injury

BackgroundThe number of patients with diabetes or the metabolic syndrome reaches epidemic proportions. On top of their diabetic cardiomyopathy, these patients experience frequent and severe cardiac ischemia-reperfusion (IR) insults, which further aggravate their degree of heart failure. Food restriction and angiotensin-converting enzyme inhibition (ACE-I) are standard therapies in these patients but the effects on cardiac IR injury have never been investigated. In this study, we tested the hypothesis that 1° food restriction and 2° ACE-I reduce infarct size and preserve cardiac contractility after IR injury in mouse models of diabetes and the metabolic syndrome.MethodsC57Bl6/J wild type (WT) mice, leptin deficient ob/ob (model for type II diabetes) and double knock-out (LDLR-/-;ob/ob, further called DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome) were used. The effects of 12 weeks food restriction or ACE-I on infarct size and load-independent left ventricular contractility after 30 min regional cardiac ischemia were investigated. Differences between groups were analyzed for statistical significance by Student’s t-test or factorial ANOVA followed by a Fisher’s LSD post hoc test.ResultsInfarct size was larger in ob/ob and DKO versus WT. Twelve weeks of ACE-I improved pre-ischemic left ventricular contractility in ob/ob and DKO. Twelve weeks of food restriction, with a weight reduction of 35-40%, or ACE-I did not reduce the effect of IR.ConclusionACE-I and food restriction do not correct the increased sensitivity for cardiac IR-injury in mouse models of type II diabetes and the metabolic syndrome.

Low-density Lipoprotein Receptor Deficiency Causes Impaired Osteoclastogenesis and Increased Bone Mass in Mice because of Defect in Osteoclastic Cell-Cell Fusion

Osteoporosis is associated with both atherosclerosis and vascular calcification attributed to hyperlipidemia. However, the cellular and molecular mechanisms explaining the parallel progression of these diseases remain unclear. Here, we used low-density lipoprotein receptor knockout (LDLR(-/-)) mice to elucidate the role of LDLR in regulating the differentiation of osteoclasts, which are responsible for bone resorption. Culturing wild-type osteoclast precursors in medium containing LDL-depleted serum decreased receptor activator of NF-κB ligand (RANKL)-induced osteoclast formation, and this defect was additively rescued by simultaneous treatment with native and oxidized LDLs. Osteoclast precursors constitutively expressed LDLR in a RANKL-independent manner. Osteoclast formation from LDLR(-/-) osteoclast precursors was delayed, and the multinucleated cells formed in culture were smaller and contained fewer nuclei than wild-type cells, implying impaired cell-cell fusion. Despite these findings, RANK signaling, including the activation of Erk and Akt, was normal in LDLR(-/-) preosteoclasts, and RANKL-induced expression of NFATc1 (a master regulator of osteoclastogenesis), cathepsin K, and tartrate-resistant acid phosphatase was equivalent in LDLR-null and wild-type cells. In contrast, the amounts of the osteoclast fusion-related proteins v-ATPase V(0) subunit d2 and dendritic cell-specific transmembrane protein in LDLR(-/-) plasma membranes were reduced when compared with the wild type, suggesting a correlation with impaired cell-cell fusion, which occurs on the plasma membrane. LDLR(-/-) mice consistently exhibited increased bone mass in vivo. This change was accompanied by decreases in bone resorption parameters, with no changes in bone formation parameters. These findings provide a novel mechanism for osteoclast differentiation and improve the understanding of the correlation between osteoclast formation and lipids.

LDL receptor deficiency results in increased osteophyte formation during experimental osteoarthritis both under low and high cholesterol conditions

LDL receptor deficiency results in increased osteophyte formation during experimental osteoarthritis both under low and high cholesterol conditions

Role of lipid apheresis in changing times.

During the last decades, LDL-apheresis was established as an extracorporeal treatment option for patients with severe heterozygous or homozygous familial hypercholesterolemia (FH) that is resistant to conventional treatment strategies such as diet, drugs, and changes in lifestyle. Nearly half a century ago, the first LDL-apheresis treatment was performed by plasma exchange in a child with homozygous FH.At the beginning of the 1970s, the clinical advantage of regular extracorporeal LDL-elimination was demonstrated in siblings suffering from homozygous FH. These findings encouraged researchers especially from Germany and Japan to develop extracorporeal devices to selectively eliminate LDL-cholesterol in the 1980s.Although the selectivity of the currently available LDL-apheresis devices is different, the efficacy of LDL-elimination during a single treatment is rather similar and ranges between 55 and 65 % of the pretreatment LDL plasma concentration.In the 1990s, the patients regularly treated by extracorporeal LDL-elimination, diet, and drugs were included in regression studies assessed by angiography. It was shown that the combined treatment with LDL-apheresis, diet, and drugs resulted in less progression of coronary lesions than drugs and/or diet alone. However, although a tendency was evident, results did not reach criteria for significance.During the last decade, apheresis registries were established to collect data on efficiency, safety, and clinical outcome of regular long-term LDL-apheresis. The evaluation of registry data will certainly permit further insights in the therapeutic benefit of this expensive and time-consuming therapeutic approach.Furthermore, the future of LDL-apheresis will depend upon the availability of highly efficient new drugs and molecular genetic approaches such as RNA silencing of the apoB gene, whereas the liver transplantation and gene therapy of the LDL-receptor deficiency will not replace LDL-apheresis in severe familial hypercholesterolemia in the near future.

Rafting for gallstones by slowing mass transit

Rafting for gallstones by slowing mass transit

Genomics and Lipidomics of Macrophage Activation

Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions and obese adipose tissue, but the mechanisms linking lipid accumulation to inflammation are poorly understood. To investigate this relationship, the LIPID MAPS consortium performed global lipidomic and transcriptomic analysis of peritoneal macrophages in wild type and LDL receptor‐deficient mice fed either a normal diet or a high fat/high cholesterol diet. These genetic and dietary interventions dramatically altered the macrophage lipidome and transcriptome, with synergistic effects observed between the high fat diet and LDL receptor deficiency. Unexpectedly, macrophage foam cells recovered from LDL receptor‐deficient mice exhibited a de‐activated, rather than an activated inflammatory phenotype. Several lines of evidence suggest that desmosterol plays a central role in integrating the homeostatic response of peritoneal macrophages to cholesterol accumulation, acting to inhibit SREBP‐target genes that drive cholesterol biosynthesis and simultaneously promoting LXR‐dependent cholesterol efflux and anti‐inflammatory activities. Desmosterol further orchestrates a metabolic adaptation resulting in suppression of most endogenous fatty acid biosynthesis but enhanced production of oleic acid, the primary fatty acid used for cholesterol esterification, and 9Z‐palmitoleic acid, a putative lipokine that exerts insulin‐sensitizing effects in vivo. Together these findings identify integrative functions of desmosterol in the control of cholesterol and fatty acid homeostasis and inflammatory responses in the macrophage.