Faculty Bibliography
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158
Molecular Pathways Underlying Cholesterol Homeostasis
Cholesterol is an essential molecule that exerts pleiotropic actions. Although its presence is vital to the cell, its excess can be harmful and, therefore, sustaining cholesterol homeostasis is crucial to maintaining proper cellular functioning. It is well documented that high plasma cholesterol concentration increases the risk of atherosclerotic heart disease. In the last decades, several studies have investigated the association of plasma cholesterol concentrations and the risk of cardiovascular diseases as well as the signaling pathways involved in cholesterol homeostasis. Here, we present an overview of several mechanisms involved in intestinal cholesterol absorption, the regulation of cholesterol synthesis and uptake. We also discuss the importance of reverse cholesterol transport and transintestinal cholesterol transport to maintain cholesterol homeostasis and prevent atherosclerosis development. Additionally, we discuss the influence of dietary cholesterol on plasma cholesterol concentration and the new recommendations for cholesterol intake in a context of a healthy dietary pattern.
PMCID:6024674
PMID: 29899250
ISSN: 2072-6643
CID: 3154982
Regulation of macrophage immunometabolism in atherosclerosis
After activation, cells of the myeloid lineage undergo robust metabolic transitions, as well as discrete epigenetic changes, that can dictate both ongoing and future inflammatory responses. In atherosclerosis, in which macrophages play central roles in the initiation, growth, and ultimately rupture of arterial plaques, altered metabolism is a key feature that dictates macrophage function and subsequent disease progression. This Review explores how factors central to the plaque microenvironment (for example, altered cholesterol metabolism, oxidative stress, hypoxia, apoptotic and necrotic cells, and hyperglycemia) shape the metabolic rewiring of macrophages in atherosclerosis as well as how these metabolic shifts in turn alter macrophage immune-effector and tissue-reparative functions. Finally, this overview offers insight into the challenges and opportunities of harnessing metabolism to modulate aberrant macrophage responses in disease.
PMID: 29777212
ISSN: 1529-2916
CID: 3121602
Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis and Atherogenesis
PMID: 29588315
ISSN: 1524-4539
CID: 3011462
Long noncoding RNAs in lipid metabolism
PURPOSE OF REVIEW/OBJECTIVE:Noncoding RNAs have emerged as important regulators of cellular and systemic lipid metabolism. In particular, the enigmatic class of long noncoding RNAs have been shown to play multifaceted roles in controlling transcriptional and posttranscriptional gene regulation. In this review, we discuss recent advances, current challenges and future opportunities in understanding the roles of lncRNAs in the regulation of lipid metabolism during health and disease. RECENT FINDINGS/RESULTS:Despite comprising the majority of the transcriptionally active regions of the human genome, lncRNA functions remain poorly understood, with fewer than 1% of human lncRNAs functionally characterized. Broadly defined as nonprotein coding transcripts greater than 200 nucleotides in length, lncRNAs execute their functions by forming RNA-DNA, RNA-protein, and RNA-RNA interactions that regulate gene expression through diverse mechanisms, including epigenetic remodeling of chromatin, transcriptional activation or repression, posttranscriptional regulation of mRNA, and modulation of protein activity. It is now recognized that in lipid metabolism, just as in other areas of biology, lncRNAs operate to regulate the expression of individual genes and gene networks at multiple different levels. SUMMARY/CONCLUSIONS:The complexity revealed by recent studies showing how lncRNAs can alter systemic and cell-type-specific cholesterol and triglyceride metabolism make it clear that we have entered a new frontier for discovery that is both daunting and exciting.
PMCID:6077844
PMID: 29553997
ISSN: 1473-6535
CID: 3001412
Novel role for store-operated calcium entry in mitochondrial gene expression, energy production, and beta-oxidation [Meeting Abstract]
Store-operated Ca2+entry (SOCE) is a pathway for increasing intracellular Ca2+ levels regulated by stromal interaction molecule 1 (STIM1), STIM2, and the Ca2+ channel ORAI1. SOCE-deficient patients suffer from Calcium Release-Activated Calcium (CRAC) channelopathy characterized by immunodeficiency, autoimmunity, myopathy, and anhidrotic ectodermal dysplasia. Several mitochondrial enzymes/complexes depend on Ca2+ but the source of Ca2+ required for their function are not entirely clear. We recently showed a cell-intrinsic role of SOCE in human mitochondria (Maus M et al. Cell Metab. 2017;25(3):698- 712). MitoView Green showed reduced mitochondrial volume in fibroblasts of patients with ORAI1/STIM1 lossof- function mutations. mtDNA copy numbers and mRNAs expression of selected mitochondrial transcription factors were normal. SDS-PAGE/Western blot analysis showed reduced expression of NADH ubiquinone oxidoreductase subunit-B8, Cytochrome b-c1 complex subunit-2, Cytochrome c oxidase subunit-I, Cytochrome C, Mitochondrial porin and permeability transition pore, etc. Blue native PAGE of isolated mitochondria confirmed reduced expression of CI, CIV and supercomplex CICIII2. SOCE-deficient fibroblasts had reduced mRNA and protein expression of uncoupling protein 2, higher basal mitochondrial membrane potential (MMP) and higher numbers of damaged mitochondria as suggested by increased co-localization of mitochondria and lysosomes and increased MitoKeima reporter activity indicative of lysosomal mitophagy. Oligomycininduced ATP-synthase inhibition revealed decreased electron transport and proton pumping rates measured as MMP hyperpolarization rates and reduced superoxide production assessed by MitoSOX. Maximal O2 consumption rates in SOCE-deficient cells were decreased. Skeletal myocytes had reduced CI and CIV function in 2 out of 3 ORAI1-deficient patients. Gene expression of very long chain acyl-CoA dehydrogenase and long-chain fatty acid transporter carnitine palmitoyltransferase 1B was reduced in patient fibroblasts cultured in either high glucose medium or oleic acid (OA) medium followed by starvation in 2 mM glucose medium. Furthermore, SOCE-deficient fibroblasts were lacking a starvation-induced increase in etomoxir-sensitive mitochondrial respiration in OA medium and showed reduced rates of OA beta-oxidation when cultured in 14C-OA-medium with or without subsequent starvation. Our findings indicate an important new role of SOCE in mitochondrial function
EMBASE:623678292
ISSN: 2326-4594
CID: 3271982
NOVEL ROLE FOR STORE-OPERATED CALCIUM ENTRY IN REGULATION OF THE LIPID METABOLISM [Meeting Abstract]
ISI:000412595402112
ISSN: 1663-2826
CID: 2746132
Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression
Atherosclerosis is a chronic inflammatory disease, and developing therapies to promote its regression is an important clinical goal. We previously established that atherosclerosis regression is characterized by an overall decrease in plaque macrophages and enrichment in markers of alternatively activated M2 macrophages. We have now investigated the origin and functional requirement for M2 macrophages in regression in normolipidemic mice that received transplants of atherosclerotic aortic segments. We compared plaque regression in WT normolipidemic recipients and those deficient in chemokine receptors necessary to recruit inflammatory Ly6Chi (Ccr2-/- or Cx3cr1-/-) or patrolling Ly6Clo (Ccr5-/-) monocytes. Atherosclerotic plaques transplanted into WT or Ccr5-/- recipients showed reduced macrophage content and increased M2 markers consistent with plaque regression, whereas plaques transplanted into Ccr2-/- or Cx3cr1-/- recipients lacked this regression signature. The requirement of recipient Ly6Chi monocyte recruitment was confirmed in cell trafficking studies. Fate-mapping and single-cell RNA sequencing studies also showed that M2-like macrophages were derived from newly recruited monocytes. Furthermore, we used recipient mice deficient in STAT6 to demonstrate a requirement for this critical component of M2 polarization in atherosclerosis regression. Collectively, these results suggest that continued recruitment of Ly6Chi inflammatory monocytes and their STAT6-dependent polarization to the M2 state are required for resolution of atherosclerotic inflammation and plaque regression.
PMCID:5531402
PMID: 28650342
ISSN: 1558-8238
CID: 2614572
Vitamin A mediates conversion of monocyte-derived macrophages into tissue-resident macrophages during alternative activation
It remains unclear whether activated inflammatory macrophages can adopt features of tissue-resident macrophages, or what mechanisms might mediate such a phenotypic conversion. Here we show that vitamin A is required for the phenotypic conversion of interleukin 4 (IL-4)-activated monocyte-derived F4/80intCD206+PD-L2+MHCII+ macrophages into macrophages with a tissue-resident F4/80hiCD206-PD-L2-MHCII-UCP1+ phenotype in the peritoneal cavity of mice and during the formation of liver granulomas in mice infected with Schistosoma mansoni. The phenotypic conversion of F4/80intCD206+ macrophages into F4/80hiCD206- macrophages was associated with almost complete remodeling of the chromatin landscape, as well as alteration of the transcriptional profiles. Vitamin A-deficient mice infected with S. mansoni had disrupted liver granuloma architecture and increased mortality, which indicates that failure to convert macrophages from the F4/80intCD206+ phenotype to F4/80hiCD206- may lead to dysregulated inflammation during helminth infection.
PMCID:5475284
PMID: 28436955
ISSN: 1529-2916
CID: 2544022
Arteriosclerosis, thrombosis, & vascular biology. 2017:37(6):1058-1067.DOI: 10.1161/ATVBAHA.116.308916
microRNA-33 Regulates Macrophage Autophagy in Atherosclerosis
OBJECTIVE: Defective autophagy in macrophages leads to pathological processes that contribute to atherosclerosis, including impaired cholesterol metabolism and defective efferocytosis. Autophagy promotes the degradation of cytoplasmic components in lysosomes and plays a key role in the catabolism of stored lipids to maintain cellular homeostasis. microRNA-33 (miR-33) is a post-transcriptional regulator of genes involved in cholesterol homeostasis, yet the complete mechanisms by which miR-33 controls lipid metabolism are unknown. We investigated whether miR-33 targeting of autophagy contributes to its regulation of cholesterol homeostasis and atherogenesis. APPROACH AND RESULTS: Using coherent anti-Stokes Raman scattering microscopy, we show that miR-33 drives lipid droplet accumulation in macrophages, suggesting decreased lipolysis. Inhibition of neutral and lysosomal hydrolysis pathways revealed that miR-33 reduced cholesterol mobilization by a lysosomal-dependent mechanism, implicating repression autophagy. Indeed, we show that miR-33 targets key autophagy regulators and effectors in macrophages to reduce lipid droplet catabolism, an essential process to generate free cholesterol for efflux. Notably, miR-33 regulation of autophagy lies upstream of its known effects on ABCA1 (ATP-binding cassette transporter A1)-dependent cholesterol efflux, as miR-33 inhibitors fail to increase efflux on genetic or chemical inhibition of autophagy. Furthermore, we find that miR-33 inhibits apoptotic cell clearance via an autophagy-dependent mechanism. Macrophages treated with anti-miR-33 show increased efferocytosis, lysosomal biogenesis, and degradation of apoptotic material. Finally, we show that treating atherosclerotic Ldlr-/- mice with anti-miR-33 restores defective autophagy in macrophage foam cells and plaques and promotes apoptotic cell clearance to reduce plaque necrosis. CONCLUSIONS: Collectively, these data provide insight into the mechanisms by which miR-33 regulates cellular cholesterol homeostasis and atherosclerosis.
PMCID:5494696
PMID: 28428217
ISSN: 1524-4636
CID: 2532752
Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism
Mycobacterium tuberculosis (Mtb) survives in macrophages by evading delivery to the lysosome and promoting the accumulation of lipid bodies, which serve as a bacterial source of nutrients. We found that by inducing the microRNA (miRNA) miR-33 and its passenger strand miR-33*, Mtb inhibited integrated pathways involved in autophagy, lysosomal function and fatty acid oxidation to support bacterial replication. Silencing of miR-33 and miR-33* by genetic or pharmacological means promoted autophagy flux through derepression of key autophagy effectors (such as ATG5, ATG12, LC3B and LAMP1) and AMPK-dependent activation of the transcription factors FOXO3 and TFEB, which enhanced lipid catabolism and Mtb xenophagy. These data define a mammalian miRNA circuit used by Mtb to coordinately inhibit autophagy and reprogram host lipid metabolism to enable intracellular survival and persistence in the host.
PMCID:4873392
PMID: 27089382
ISSN: 1529-2916
CID: 2079882
