正常组织中过多脂质的清除方法，包括β氧化、巨噬细胞吞噬等

目的 探讨miR-125a对巨噬细胞脂质代谢及主动脉粥样硬化（atherosclerosis，AS）病变的影响及作用机制。 方法 油红O及比色法检测巨噬细胞内脂滴情况及脂质含量；生物信息学预测miR-125a下游靶标；双荧光素酶报告基因验证miR-125a与sortilin mRNA靶向结合；qPCR、Western blot and 免疫组化检测荷脂THP-1巨噬细胞和低密度脂蛋白受体敲除（LDLR?/?）小鼠中miR-125a及sortilin表达；全自动生化分析仪测定血脂改变；组织染色显示主动脉AS斑块面积及脂质沉积情况。 结果 过表达miR-125a可减轻THP-1巨噬细胞内脂质蓄积；生信分析和荧光素酶报告基因显示sortilin mRNA是miR-125a的作用靶标；过表达miR-125a可下调巨噬细胞sortilin表达，减少胞内脂滴数量及脂质含量，改善LDLR?/?小鼠血脂谱，抑制主动脉脂质沉积及AS病变面积。 结论 miR-125a可通过下调sortilin表达抑制巨噬细胞脂质蓄积及主动脉AS病变。

… Although a large number of studies have described the relationship between lipophagy and hepatic lipid homeostasis, the degree of steatosis has not been reduced or even altered in …

Lipid droplets (LDs), initially considered “inert” lipid deposits, have gained during the last decade the classification of cytosolic organelles due to their defined composition and the multiplicity of specific cellular functions in which they are involved. The classification of LD as organelles brings along the need for their regulated turnover and recent findings support the direct contribution of autophagy to this turnover through a process now described as lipophagy. This paper focuses on the characteristics of this new type of selective autophagy and the cellular consequences of the mobilization of intracellular lipids through this process. Lipophagy impacts the cellular energetic balance directly, through lipid breakdown and, indirectly, by regulating food intake. Defective lipophagy has been already linked to important metabolic disorders such as fatty liver, obesity and atherosclerosis, and the age-dependent decrease in autophagy could underline the basis for the metabolic syndrome of aging.

… Lipid homeostasis is crucial, such that excess fatty acids (… lipophagy, offering novel insights into this rapidly growing field. This article is part of a Special Issue entitled: The cellular lipid …

Lipophagy, the selective autophagic degradation of lipid droplets (LDs), is a key mechanism for lipid homeostasis and cellular adaptation to metabolic and stress conditions. In mammals, lipophagy is governed by signaling pathways, LD-associated receptors (e.g. SQSTM1/p62, NBR1, OPTN, SPART, OSBPL8, DDHD2, VPS4A, ATG14, and TP53INP2), and transcription factors (TFEB, TFE3, FOXO1, PPARA, PPARG, and SREBF1/SREBP1) that coordinate LD recognition, sequestration, and lysosomal degradation. Dysregulated lipophagy contributes to the pathogenesis of metabolic and age-related diseases, including metabolic dysfunction-associated steatotic liver disease/nonalcoholic fatty liver disease (MASLD/NAFLD), alcoholic liver disease, diabetes, atherosclerosis, neurodegeneration and cancer. Several recent reviews have discussed lipophagy from different angles, including its roles in metabolic disorders, central nervous system diseases, and fundamental mechanisms across species. In contrast, this review focuses specifically on mammalian lipophagy by synthesizing the latest mechanistic insights into receptor-mediated recognition, transcriptional regulation, and signaling integration. We also outline unresolved questions and conceptual gaps - such as how lipophagy is selectively activated, how it coordinates with lipolysis, and whether distinct receptor codes exist in tissue- and disease-specific contexts - that remain unanswered in the current literature.

The selective breakdown by autophagy of lipid droplet-stored lipids termed lipophagy is a lysosomal lipolytic pathway that complements the actions of cytosolic neutral lipases. The physiological importance of lipophagy has been demonstrated in multiple mammalian cell types, as well as in lower organisms, and this pathway has many functions in addition to supplying free fatty acids to maintain cellular energy stores. Recent studies have begun to delineate the molecular mechanisms of the selective recognition of lipid droplets by the autophagic machinery, and the intricate crosstalk that exists among the forms of autophagy and neutral lipases. These studies have led to increased interest in the role of lipophagy in both human disease pathogenesis and therapy.

Ischemic-reperfusion (I/R) injury induced a remodeling of protein and lipid homeostasis, under oxidative stress and inflammatory status. Starvation occurring during I/R is a condition leading to autophagy activation, which allows abnormal material clearance or amino acid, or both, and fatty acid (FA) recycling essential for survival. This study investigated the lipid reshaping, peroxidation, and related-signaling pathways, in rat brain endothelial cells (RBE4) subjected to 3 h of oxygen and glucose deprivation (OGD) and restoration of standard condition (I/R in vitro model). Lipids and proteins were analyzed after 1 or 24 h of oxygen and nutrient restoration. Together with the oxidative stress and inflammatory status, I/R injury induced a reshaping of neutral lipids and biogenesis of lipid droplets (LD) with excessive lipid storage. The increase of LC3-II/LC3-I ratio, an autophagy marker, and LC3 co-localization with LD suggest the activation of lipophagy machinery to counteract the cell engulfment. Lipophagy leads to cholesterol ester (CE) hydrolysis, increasing free cholesterol (FC) secretion, which occurred by specific transporters or unconventional exocytosis pathways, or both. Here, we propose that an unconventional spreading of FC and other lipid metabolites may influence the neurovascular unit (NVU) cells, contributing to Blood brain barrier (BBB) alteration or adaptation, or both, to the cumulative effects of several transient ischemia.

Significance Lipid droplets (LDs) are specialized fat-storage organelles that can be used as a fuel source by many types of cells when nutrients are scarce. One mechanism used by hepatocytes (the functional cells of the liver) for the catabolism of these energy reserves is the lysosome-directed process of autophagy. Traditionally, autophagy necessitates the enclosure of cargo within a double-membrane autophagosome before delivery to the lysosome for degradation. Here, we use live-cell and electron microscopy to demonstrate that stable contacts between LDs and lysosomes in hepatocytes can result in the transfer of both proteins and lipids from LDs directly into the lysosome in the absence of an autophagosomal intermediate. These findings reveal a mechanism used for lipid homeostasis in the liver.

Lipid metabolism disorders are considerably involved in the pathology of atherosclerosis; nevertheless, the fundamental mechanism is still largely unclear. This research sought to examine the function of lipophagy in lipid metabolism disorder-induced atherosclerosis and its fundamental mechanisms. Previously, Sirt6 has been reported to stimulate plaque stability by promoting macrophage autophagy. However, its role in macrophage lipophagy and its relationship with Wnt1 remains to be established. In this study, ApoE^−/−: Sirt6^−/− and ApoE^−/−: Sirt6Tg mice were used and lipid droplets were analysed via transmission electron microscopy and Bodipy 493/503 staining in vitro. Atherosclerotic plaques in ApoE^−/−: Sirt6^−/− mice showed greater necrotic cores and lower stability score. Reconstitution of Sirt6 in atherosclerotic mice improved lipid metabolism disorder and prevented the progression of atherosclerosis. Furthermore, macrophages with Ac-LDL intervention showed more lipid droplets and increased expression of adipophilin and PLIN2. Reconstitution of Sirt6 recruited using SNF2H suppressed Wnt1 expression and improved lipid metabolism disorder by promoting lipophagy. In addition, downregulation of Sirt6 expression in Ac-LDL-treated macrophages inhibited lipid droplet degradation and stimulated foam cell formation. Innovative discoveries in the research revealed that atherosclerosis is caused by lipid metabolism disorders due to downregulated Sirt6 expression. Thus, modulating Sirt6’s function in lipid metabolism might be a useful therapeutic approach for treating atherosclerosis.

… nor have more than a few of the 33 requn'ed reacuons been experimentally verdied Observauons made by Kunau and Bartmk2 on the retroconvers~on of polyunsaturated fatty acids …

… compartment to yield free fatty acids. The mechanism of fatty acid uptake by animal cells, … will provide an understanding of the mechanism of fatty acid uptake. The identification of …

… (3-oxidation of polyunsaturated fatty acids. The degradation of unsaturated fatty acids by 8-… the enzymes required for the breakdown of saturated fatty acids (1). The auxiliary enzymes …

… Schematic diagram depicting the different mechanisms by which fatty acids can be oxidized … General aspects of fatty acid oxidation Beta-oxidation is the preferred way of oxidizing FAs. …

Peroxisomes were purified by differential and equilibrium density centrifugation from the livers of rats treated with clofibrate to enhance their peroxisomal system of fatty acid oxidation. These purified peroxisomes were tested for the presence of crotonase, beta-hydroxybutyryl-CoA dehydrogenase and thiolase using spectroscopic techniques that utilize the characteristic absorption bands of the appropriate 4-carbon acyl-CoA substrates. All three enzymes were found. Analysis of the fractions from equilibrium density centrifugation revealed major peaks of these enzyme activities in peroxisomes and excluded contamination by mitochondria as an explanation of the results. In the presence of excess CoA the purified peroxisomes oxidized palmitoyl-CoA to acetyl-CoA, and reduced NAD, with a 1:5:5 stoichiometry. The peroxisomes were inactive with butyryl-CoA and less active with octanoyl-CoA than with lauroyl-CoA or palmitoyl-CoA; they appear specialized for the beta oxidation of long chain fatty acids.

… Fatty acid synthesis and catabolism (by fatty acid oxidation) are normal part of basic fuel metabolism in animals. Fatty acids … The increase in fatty acid β-oxidation is negatively correlated …

In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty acid β-oxidation pathway, a distinct mitochondrial system feeds the oxidative phosphorylation pathway for ATP synthesis. At the same time, the peroxisomal β-oxidation pathway participates in cellular thermogenesis. A scientific milestone in 1965 helped discover the hepatomegaly effect in rat liver by clofibrate, subsequently identified as a peroxisome proliferator in rodents and an activator of the peroxisomal fatty acid β-oxidation pathway. These peroxisome proliferators were later identified as activating ligands of Peroxisome Proliferator-Activated Receptor α (PPARα), cloned in 1990. The ligand-activated heterodimer PPARα/RXRα recognizes a DNA sequence, called PPRE (Peroxisome Proliferator Response Element), corresponding to two half-consensus hexanucleotide motifs, AGGTCA, separated by one nucleotide. Accordingly, the assembled complex containing PPRE/PPARα/RXRα/ligands/Coregulators controls the expression of the genes involved in liver peroxisomal fatty acid β-oxidation. This review mobilizes a considerable number of findings that discuss miscellaneous axes, covering the detailed expression pattern of PPARα in species and tissues, the lessons from several PPARα KO mouse models and the modulation of PPARα function by dietary micronutrients.

The metabolic network of a living cell is highly intricate and involves complex interactions between various pathways. In this study, we propose a computational model that integrates glycolysis, the pentose phosphate pathway (PPP), the fatty acids beta-oxidation, and the tricarboxylic acid cycle (TCA cycle) using queueing theory. The model utilizes literature data on metabolite concentrations and enzyme kinetic constants to calculate the probabilities of individual reactions occurring on a microscopic scale, which can be viewed as the reaction rates on a macroscopic scale. However, it should be noted that the model has some limitations, including not accounting for all the reactions in which the metabolites are involved. Therefore, a genetic algorithm (GA) was used to estimate the impact of these external processes. Despite these limitations, our model achieved high accuracy and stability, providing real-time observation of changes in metabolite concentrations. This type of model can help in better understanding the mechanisms of biochemical reactions in cells, which can ultimately contribute to the prevention and treatment of aging, cancer, metabolic diseases, and neurodegenerative disorders.

… The mechanism of enhanced peroxisomal beta-oxidation by … The effect of the type of fatty acid on the rates of beta-oxidation … fatty acid type represent means + SEM of beta-oxidation …

… Our understanding of the mechanism of this association between fatty acid oxidation defects in … of two critical enzymes involved in beta-oxidation of fatty acids: long chain 3-hydroxyacyl-…

… which lead to disruption of the beta oxidation of fatty acids. The underlying pathogenetic mechanism is either a defect in an enzyme of the beta oxidation cycle or a defect in carnitine …

… was to evaluate the importance of fatty acid beta-oxidation (FAO) in the cumulus oocyte … meet the metabolic demands of the COCs when fatty acid metabolism is compromised. Our data …

Fatty acids, such as short-chain fatty acids, medium-chain fatty acids and long-chain fatty acids, exist in different chain lengths and with various modifications, which determine their physical, metabolic and biological properties. They serve as important nutrients in energy production via mitochondrial beta-oxidation in various cell types including immune cells. At optimal levels in the body, fatty acids support normal differentiation and function of immune cells. However, at excessive levels, they can cause dysregulation of immune cells and inflammation. The three types of fatty acids regulate cells, in part, via the activation of G protein-coupled receptors, such as GPR41, GPR43, GPR109A, and Olfr78 for short-chain, GPR40 and GPR120 for both medium- and long-chain fatty acids, and GPR84 for medium-chain fatty acids. Activation of these receptors by fatty acids regulates cell proliferation and cell-specific functions. Importantly, fatty acids induce the production of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide through activation of G-protein coupled receptors. Short-chain fatty acids additionally control epigenetic regulators such as histone deacetylases and histone acetyltransferases. Saturated long-chain fatty acids and omega-6 polyunsaturated fatty acids are implicated in metabolic diseases and inflammatory conditions, whereas short-chain fatty acids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids are generally associated with functional immunity with anti-inflammatory effects. This article explores how fatty acids regulate the immune system, focusing on their common and unique roles, as well as their opposing functions.

… macrophage lipid efflux, we analyzed apoAI-dependent cholesterol efflux in wild-type and PPARγ −/− ES–derived macrophages… to stimulate cholesterol efflux was completely abolished …

… efflux assays. We observed a strong induction of apoA-I-dependent lipid efflux in stimulated macrophages, implicating an important role for retinoids in cellular functions of macrophages…

… that mobilize lipid droplet cholesterol for efflux in macrophage foam … for efflux in lipid-loaded macrophages. In the case of acid lipolysis (A), autophagic sequestration of cytoplasmic lipid …

… Here, we identify lipid-laden microglia/macrophages as a metabolically stressed inflammatory state that emerges after SCI and investigate the role of lipid efflux in regulating this process…

Mechanisms of lipid homeostasis and its impairment are of crucial importance for atherogenesis, and their understanding is necessary for successful development of new therapeutic approaches. In the arterial wall, macrophages play a prominent role in intracellular lipid accumulation, giving rise to foam cells that populate growing atherosclerotic plaques. Under normal conditions, macrophages are able to process substantial amounts of lipids and cholesterol without critical overload of the catabolic processes. However, in atherosclerosis, these pathways become inefficient, leading to imbalance in cholesterol and lipid metabolism and disruption of cellular functions. In this review, we summarize the existing knowledge on the involvement of macrophage lipid metabolism in atherosclerosis development, including both the results of recent studies and classical concepts, and provide a detailed description of these processes from the moment of lipid uptake with lipoproteins to cholesterol efflux.

ABSTRACT Macrophage autophagy is a highly anti-atherogenic process that promotes the catabolism of cytosolic lipid droplets (LDs) to maintain cellular lipid homeostasis. Selective autophagy relies on tags such as ubiquitin and a set of selectivity factors including selective autophagy receptors (SARs) to label specific cargo for degradation. Originally described in yeast cells, “lipophagy” refers to the degradation of LDs by autophagy. Yet, how LDs are targeted for autophagy is poorly defined. Here, we employed mass spectrometry to identify lipophagy factors within the macrophage foam cell LD proteome. In addition to structural proteins (e.g., PLIN2), metabolic enzymes (e.g., ACSL) and neutral lipases (e.g., PNPLA2), we found the association of proteins related to the ubiquitination machinery (e.g., AUP1) and autophagy (e.g., HMGB, YWHA/14-3-3 proteins). The functional role of candidate lipophagy factors (a total of 91) was tested using a custom siRNA array combined with high-content cholesterol efflux assays. We observed that knocking down several of these genes, including Hmgb1, Hmgb2, Hspa5, and Scarb2, significantly reduced cholesterol efflux, and SARs SQSTM1/p62, NBR1 and OPTN localized to LDs, suggesting a role for these in lipophagy. Using yeast lipophagy assays, we established a genetic requirement for several candidate lipophagy factors in lipophagy, including HSPA5, UBE2G2 and AUP1. Our study is the first to systematically identify several LD-associated proteins of the lipophagy machinery, a finding with important biological and therapeutic implications. Targeting these to selectively enhance lipophagy to promote cholesterol efflux in foam cells may represent a novel strategy to treat atherosclerosis. Abbreviations: ADGRL3: adhesion G protein-coupled receptor L3; agLDL: aggregated low density lipoprotein; AMPK: AMP-activated protein kinase; APOA1: apolipoprotein A1; ATG: autophagy related; AUP1: AUP1 lipid droplet regulating VLDL assembly factor; BMDM: bone-marrow derived macrophages; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; BSA: bovine serum albumin; CALCOCO2: calcium binding and coiled-coil domain 2; CIRBP: cold inducible RNA binding protein; COLGALT1: collagen beta(1-O)galactosyltransferase 1; CORO1A: coronin 1A; DMA: deletion mutant array; Faa4: long chain fatty acyl-CoA synthetase; FBS: fetal bovine serum; FUS: fused in sarcoma; HMGB1: high mobility group box 1; HMGB2: high mobility group box 2: HSP90AA1: heat shock protein 90: alpha (cytosolic): class A member 1; HSPA5: heat shock protein family A (Hsp70) member 5; HSPA8: heat shock protein 8; HSPB1: heat shock protein 1; HSPH1: heat shock 105kDa/110kDa protein 1; LDAH: lipid droplet associated hydrolase; LIPA: lysosomal acid lipase A; LIR: LC3-interacting region; MACROH2A1: macroH2A.1 histone; MAP1LC3: microtubule-associated protein 1 light chain 3; MCOLN1: mucolipin 1; NBR1: NBR1, autophagy cargo receptor; NPC2: NPC intracellular cholesterol transporter 2; OPTN: optineurin; P/S: penicillin-streptomycin; PLIN2: perilipin 2; PLIN3: perilipin 3; PNPLA2: patatin like phospholipase domain containing 2; RAB: RAB, member RAS oncogene family; RBBP7, retinoblastoma binding protein 7, chromatin remodeling factor; SAR: selective autophagy receptor; SCARB2: scavenger receptor class B, member 2; SGA: synthetic genetic array; SQSTM1: sequestosome 1; TAX1BP1: Tax1 (human T cell leukemia virus type I) binding protein 1; TFEB: transcription factor EB; TOLLIP: toll interacting protein; UBE2G2: ubiquitin conjugating enzyme E2 G2; UVRAG: UV radiation resistance associated gene; VDAC2: voltage dependent anion channel 2; VIM: vimentin

Macrophages are the predominant cellular component of atherosclerotic lesions, where they scavenge oxidatively modified lipoproteins while defending themselves against cholesterol-induced cytotoxicity by adaptive mechanisms that depend in part on the synthesis, distribution and efflux of phosphatidylcholines. PC-TP (phosphatidylcholine transfer protein) is a START (steroidogenic acute regulatory protein-related lipid transfer) domain protein that catalyses the intermembrane transfer of phosphatidylcholines and promotes apolipoprotein AI-mediated lipid efflux when overexpressed in the cytosol of Chinese-hamster ovary cells. To explore a role for PC-TP in the adaptive responses of macrophages to cholesterol loading, we utilized peritoneal macrophages from mice with homozygous disruption of the gene encoding PC-TP (Pctp−/−) and wild-type littermate controls. PC-TP was abundantly expressed in macrophages from wild-type but not Pctp−/− mice. In cholesteryl ester-loaded macrophages from Pctp−/− mice, the apolipoprotein AI-mediated efflux of phospholipids and cholesterol was decreased. This could be attributed to proportional decreases in the expression levels of ATP-binding cassette A1. Also, in response to free cholesterol loading, the absence of PC-TP from macrophages was associated with marked increases in apoptotic cell death. These findings suggest that PC-TP in macrophages may serve an atheroprotective role by defending against cholesterol-induced cytotoxicity.

… content is not sufficient to promote cholesterol efflux to lipid-poor apoA-1. Whereas some … lipid efflux to apoA-1. Interestingly, suppression of ABCG1 expression in cholesterol-loaded …

Macrophage foam cells (i.e., cholesteryl ester-laden macrophages) are abundant in atherosclerotic plaques, and increased macrophage foam cell content is associated with plaque instability (1, 2). Macrophages are generally thought to unload surplus cholesterol via efflux mediated by the ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) to apolipoprotein A1 [apoA1 (3, 4)] and high-density lipoproteins [HDLs (5, 6)], respectively. Several studies in large-population cohorts have shown that the cholesterol efflux capacity of HDL (i.e., its potential to act as an acceptor for cholesterol efflux from macrophages) is an inverse predictor of cardiovascular disease (7⇓–9), highlighting the importance of cholesterol efflux as an atheroprotective mechanism. In PNAS, He et al. (10) describe a mechanism for macrophage cholesterol efflux, which involves the transfer of surplus cholesterol from the macrophage plasma membrane to the plasma membrane and cytosolic lipid droplets of adjacent smooth muscle cells (SMCs). This transcellular cholesterol movement (TCM) could represent a mode that macrophages and perhaps other cell types use to unload excessive cholesterol, helping to prevent potential toxicity associated with excessive cholesterol accumulation and in atherosclerotic plaques helping to reverse the formation of macrophage foam cells. The discovery of TCM was made possible by the use of sophisticated technology (nano-secondary ion mass spectrometry [NanoSIMS] imaging) that allows microscopic colocalization of 13C-cholesterol with 15N-choline (11). As such, the transfer of 13C-cholesterol from macrophages to adjacent SMCs that were metabolically labeled with 15N-choline could be imaged (15N-choline is incorporated into the SMC membrane components phosphatidylcholine and sphingolipids). Within atherosclerotic plaques, macrophages or monocytes could unload their surplus cholesterol onto adjacent SMCs, leading to reversal of macrophage foam cell formation, which … [↵][1]1To whom correspondence may be addressed. Email: m.westerterp{at}umcg.nl or art1{at}cumc.columbia.edu. [1]: #xref-corresp-1-1

Trans fatty acid consumption is associated with an increased risk of coronary heart disease. This increased risk has been attributed to decreased levels of HDL cholesterol and increased levels of LDL cholesterol. However, the mechanism by which trans fatty acid modulates cholesterol transit remains poorly defined. ATP-binding cassette transporter A1 (ABCA1)-mediated macrophage cholesterol efflux is the rate-limiting step initiating apolipoprotein A-I lipidation. In this study, elaidic acid, the most abundant trans fatty acid in partially hydrogenated vegetable oil, was shown to stabilize macrophage ABCA1 protein levels in comparison to that of its cis fatty acid isomer, oleic acid. The mechanism responsible for the disparate effects of oleic and elaidic acid on ABCA1 levels was through accelerated ABCA1 protein degradation in cells treated with oleic acid. In contrast, no apparent differences were observed in ABCA1 mRNA levels, and only minor changes were observed in Liver X receptor/Retinoic X receptor promoter activity in cells treated with elaidic and oleic acid. Efflux of both tracers and cholesterol mass revealed that elaidic acid slightly increased ABCA1-mediated cholesterol efflux, while oleic acid led to decreased ABCA1-mediated efflux. In conclusion, these studies show that cis and trans structural differences in 18 carbon n-9 monoenoic fatty acids variably impact cholesterol efflux through disparate effects on ABCA1 protein degradation.

ABCA7 is homologous to ABCA1 and has recently been shown in cell culture to bind apolipoprotein A-I (apoA-I) and to promote the efflux of phospholipids. However, it is not known if ABCA7 promotes lipid efflux in vivo. When expressed in HEK293 cells, both human and mouse ABCA7 promoted phospholipid efflux to apoA-I but no detectable cholesterol efflux. However, genetic knockdown of ABCA7 in mouse peritoneal macrophages did not affect phospholipid or cholesterol efflux to apoA-I. Moreover, in ABCA1-knockout macrophages, there was no detectable apoA-I-stimulated phospholipid efflux, inconsistent with a residual role of ABCA7. In contrast to plasma membrane localization of ABCA7 in transfected embryonic kidney cells, immunofluorescence microscopy of endogenous ABCA7 in macrophages showed a predominantly intracellular localization of the protein. Strikingly, immunofluorescence studies of adult mouse kidney revealed an apical brush border membrane localization of ABCA7 in the proximal tubule, suggesting that ABCA7 may come in contact with apoA-I in the glomerular filtrate. Although ABCA7 does not contribute to apolipoprotein-mediated lipid efflux in resting macrophages, its cell surface location in the kidney suggests that it could serve such a role in tissue microenvironments.

… lipid-free apoAI) that can directly promote cholesterol efflux via ABCA1. However, we cannot exclude the possibility that such species are generated from HDL when it is incubated with …

… ABCG1 play a pivotal role in this process by effluxing lipids from foam cells to apoA-I and HDL, … In macrophages, ABCA1 and ABCG1 prevent the excessive accumulation of lipids and …

The clearance of free cholesterol from plasma lipoproteins by tissues is of major quantitative importance, but it is not known whether this is passive or receptor-mediated. Based on our finding that scavenger receptor BI (SR-BI) promotes free cholesterol (FC) exchange between high density lipoprotein (HDL) and cells, we tested whether SR-BI would effect FC movement in vivo using [14C]FC- and [3H]cholesteryl ester (CE)-labeled HDL in mice with increased (SR-BI transgenic (Tg)) or decreased (SR-BI attenuated (att)) hepatic SR-BI expression. The initial clearance of HDL FC was increased in SR-BI Tg mice by 72% and decreased in SR-BI att mice by 53%, but was unchanged in apoA-I knockout mice compared with wild-type mice. Transfer of FC to non-HDL and esterification of FC were minor and could not explain differences. The hepatic uptake of FC was increased in SR-BI Tg mice by 34% and decreased in SR-BI att mice by 22%. CE clearance and uptake gave similar results, but with much slower rates. The uptake of HDL FC and CE by SR-BI Tg primary hepatocytes was increased by 2.2- and 2.6-fold (1-h incubation), respectively, compared with control hepatocytes. In SR-BI Tg mice, the initial biliary secretion of [14C]FC was markedly increased, whereas increased [3H]FC appeared after a slight delay. Thus, in the mouse, a major portion of the clearance of HDL FC from plasma is mediated by SR-BI.

In order to assess the presence of specific recognition sites for high density lipoprotein (HDL) in vivo, HDL was nitrosylated with tetranitromethane and the decay and liver uptake were compared with that of native HDL. The association of intravenously injected nitrosylated HDL (TNM-HDL) with liver was greatly increased as compared to native HDL. Using a cold cell isolation method, it became evident that the liver endothelial cells were responsible for the increased uptake of the modified HDL. The involvement of the endothelial cells in the uptake of TNM-HDL from the circulation could also be demonstrated morphologically by using the fluorescent dye dioctadecyl-tetramethyl-indocarbocyanine perchlorate (Dil) to label HDL. In vitro competition studies with isolated liver endothelial cells indicated that unlabeled modified HDL and acetylated LDL displaced iodine-labeled TNM-HDL, while no competition was seen with LDL and a slight displacement was seen with unlabeled native HDL. Nonlipoprotein competitors of the scavenger receptor such as fucoidin and polyinosinic acid blocked the interaction of TNM-HDL with the liver endothelial cells. Also the degradation of TNM-HDL was blocked by low concentrations of chloroquine. It can be concluded that a scavenger receptor on liver endothelial cells is involved in the clearance of tetranitromethane-modified HDL, which excludes the possibility of using TNM-HDL in vivo to assess the non-receptor-dependent uptake of HDL. The use of nitrosylated HDL in vitro as a low affinity control is limited to cell types that do not possess scavenger receptors, because cell types with scavenger receptors will recognize and internalize TNM-HDL by a high affinity scavenger pathway.

… ) take up modified cholesterol-rich lipoproteins via scavenger receptors (SRs). KCs thereby … mainly depends on CD36 and macrophage scavenger receptor 1. METHODS: To evaluate …

… Scavenger receptor class B type I (SR-BI) has been found to be an authentic HDL receptor that mediates the selective uptake of HDL CE and the bi-directional transfer of free …

The scavenger receptor class B type I (SR-BI), which is expressed in the liver and intestine, plays a critical role in cholesterol metabolism in rodents. While hepatic SR-BI expression controls high density lipoprotein (HDL) cholesterol metabolism, intestinal SR-BI has been proposed to facilitate cholesterol absorption. To evaluate further the relevance of SR-BI in the enterohepatic circulation of cholesterol and bile salts, we studied biliary lipid secretion, hepatic sterol content and synthesis, bile acid metabolism, fecal neutral sterol excretion, and intestinal cholesterol absorption in SR-BI knockout mice. SR-BI deficiency selectively impaired biliary cholesterol secretion, without concomitant changes in either biliary bile acid or phospholipid secretion. Hepatic total and unesterified cholesterol contents were slightly increased in SR-BI-deficient mice, while sterol synthesis was not significantly changed. Bile acid pool size and composition, as well as fecal bile acid excretion, were not altered in SR-BI knockout mice. Intestinal cholesterol absorption was somewhat increased and fecal sterol excretion was slightly decreased in SR-BI knockout mice relative to controls. These findings establish the critical role of hepatic SR-BI expression in selectively controlling the utilization of HDL cholesterol for biliary secretion. In contrast, SR-BI expression is not essential for intestinal cholesterol absorption. —Mardones, P., V. Quiñones, L. Amigo, M. Moreno, J. F. Miquel, M. Schwarz, H. E. Miettinen, B. Trigatti, M. Krieger, S. VanPatten, D. E. Cohen, and A. Rigotti. Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice.

肿瘤相关巨噬细胞（tumor associated macrophages，TAMs）是实质肿瘤中最常见的间质细胞类型之一，且与肿瘤微环境的免疫抑制状态有着紧密联系，并促进肿瘤的恶性进展。TAMs内的代谢发生了重编程，并且参与调控其自身的极化以及相应的功能表型。本文详细论述了TAMs中包括三酰甘油、脂肪酸及其衍生物、胆固醇和磷脂在内的脂质代谢重编程以及它们对肿瘤进展的调控。然而，肿瘤细胞与肿瘤微环境间质细胞的代谢极具异质性。肿瘤细胞与间质细胞之间脂代谢重编程的异同点以及重编程如何调控细胞活性的机制值得深入探索。同时，综合考虑肿瘤不同的组织类型、不同的发展阶段，精准靶向干预TAMs脂质代谢重编程，促进TAMs向M1样巨噬细胞极化，将成为代谢调节肿瘤免疫治疗的新策略。

聚酮化合物（PKs）作为一大类次级代谢产物，有着重要的生物活性和潜在的应用价值。链霉菌具有合成多种聚酮化合物的潜力，但野生型菌株合成聚酮化合物的产量难以满足工业化生产的需求。贮藏脂质的降解能为聚酮化合物生物合成提供大量的酰基CoA前体，因此，控制好脂肪酸与聚酮化合物生物合成通量，有利于促进目标聚酮化合物的合成。本文综述了强化脂肪酸β-氧化途径提高聚酮化合物产量的研究进展，为利用β-氧化途径促进聚酮化合物生物合成提供了新的研究策略。

脂质代谢紊乱是驱动肥胖症、糖尿病、动脉粥样硬化等代谢性疾病发生发展的关键机制之一。近年来的研究表明靶向脂质代谢关键节点的药物干预策略展现出突破传统药物的潜力。首先简要总结了代谢性疾病相关的脂质代谢通路靶点，随后系统性地介绍了靶向肝脏、脂肪组织、巨噬细胞、动脉粥样硬化斑块等脂代谢活跃部位的新型靶向输送策略，旨在为探索更安全有效的代谢性疾病新疗法提供参考。

为探讨血府逐瘀汤对动脉粥样硬化(atherosclerosis,AS)大鼠主动脉壁细胞间黏附分子-1(ICA M-1)表达水平和脂质过氧化物的影响,将40只大鼠随机分为正常对照组、模型组、血脂康组、血府逐瘀汤高剂量组、血府逐瘀汤低剂量组,对照组饲喂正常饲料,模型组给予高脂饲料,治疗组在给予高脂饲料的同时给予治疗药物,12周后免疫组化法观察主动脉壁ICAM-1的表达水平、检测血清超氧化物歧化酶(SOD)、丙二醛(MDA)的含量.结果显示:模型组ICAM-1的表达水平呈强阳性表达,治疗组各组均呈弱阳性表达,各组间均有统计学意义(P＜0.05).治疗组SOD水平较模型组显著升高,MDA含量显著降低,各组间均有统计学意义(P＜0.05).这说明血府逐瘀汤可以通过下调ICAM-1的表达,清除脂质过氧化物、保护内皮细胞起到抗AS的作用.

目的分析紫杉醇脂质体对乳腺癌MCF-7细胞的生长抑制作用，观察药物作用的时间浓度关系并探究其作用机制。方法应用不同剂量紫杉醇脂质体对MCF-7细胞进行处理，通过MTT法检测细胞存活率，倒置显微镜观察细胞形态，流式细胞分析技术检测细胞凋亡情况及其对细胞周期的影响，Western blot法检测bcl-2蛋白表达情况。结果紫杉醇脂质体对MCF-7细胞有明显的剂量-时间依赖效应。紫杉醇与紫杉醇脂质体均可将MCF-7细胞阻滞在G2/M期，且随药物浓度增加，凋亡细胞所占比例逐渐增加。通过Western blot法检测发现，紫杉醇脂质体作用后MCF-7细胞bcl-2蛋白表达明显下降，bax蛋白表达明显上调，bax/bcl-2比例明显上调。结论与紫杉醇相比，紫杉醇以脂质体对人乳腺癌MCF-7细胞具有同样的抑制作用，其促凋亡机制之一为调控bcl-2及bax蛋白表达。

目的 研究新化合物哌芳安他的抗动脉粥样硬化作用。 方法 以主动脉大体斑块分级和光镜下动脉粥样硬化病变分级为指标,观察哌芳安他对高脂饮食诱导的兔和鹌鹑动脉粥样硬化形成的影响。 结果 可刺激NO和PGI 2 从内皮细胞释放的新化合物哌芳安他,对高血脂兔和鹌鹑血脂水平无明显影响,而能延缓高血脂诱导的兔主动脉和冠状动脉,及鹌鹑主动脉和头臂动脉的动脉粥样硬化病变形成。 结论 新化合物哌芳安他具有延缓高血脂诱发的动脉粥样硬化病变形成的作用。

[目的] 副溶血性弧菌是一种重要的人畜共患病原菌，脂蛋白定位系统（Localization of lipoprotein system，Lol）负责该菌脂蛋白的转运与定位，与其致病力及耐药性密切相关，对Lol系统转运蛋白进行系统的生物信息学分析，有助于推动副溶血性弧菌致病与耐药机理的进一步研究。 [方法] 本文通过生物信息学分析技术，结合ExPASy在线工具、SignalP 4.0 Server、TMHMM-2.0、STRING、SWISS-MODEL等软件，分析了副溶血性弧菌Lol系统转运蛋白LolA-E及LolCD 2 E的基本性质、蛋白互作关系及三级结构。 [结果] LolA和LolB为酸性亲水蛋白，含信号肽位点，无跨膜区域。LolC和LolE为碱性疏水膜蛋白，LolCD 2 E为中性疏水膜蛋白，LolC-E及LolCD 2 E均无显著的信号肽位点。蛋白相互作用网络显示，LolA-E五个蛋白的编码基因均共表达，负责脂蛋白的合成与转运，并与BamA、Pal、MacB、CmeC等外膜蛋白具有密切的互作关系。三级结构同源建模发现，副溶血性弧菌与大肠杆菌拥有相似的LolA和LolB结构，LolC-E含有MacB蛋白的同源结构，赋予了该系统消耗ATP运输脂蛋白的重要功能。此外，本研究还首次发现了副溶血性弧菌LolC和LolE中存在一段保守的Hook结构，是LolCD 2 E复合物与LolA结合并转运脂蛋白的关键区域。 [结论] 本研究为副溶血性弧菌Lol系统转运蛋白的表达纯化、结构与功能的研究提供了重要的数据基础，为后续抗菌药物的研发提供了新型作用靶点。

目的 探讨血浆载脂蛋白A1（ApoA1）∕载脂蛋白B（ApoB）值及其他血脂指标在冠心病发生和发展的作用。 方法 选取2010-2011年于天津市胸科医院行冠脉造影（CAG）的患者550例，根据CAG结果分为冠心病组和正常组，其中冠心病组包括单支病变组、双支病变组、三支病变组。分别测定患者血浆载脂蛋白A1（ApoA1），载脂蛋白B（ApoB），总胆固醇（TC），甘油三酯（TG），高密度脂蛋白胆固醇（HDL-C），低密度脂蛋白胆固醇（LDL-C）, 及载脂蛋白ApoA1∕B（ApoA1∕B）值。 结果 表明ApoA1／ApoB值与冠脉病变呈负相关（P＜0.01）；多因素Logistic回归分析证实 ApoA1∕B为冠状动脉粥样硬化的保护因子（P＜0.01）。 结论 ApoA1∕B值与冠状动脉粥样硬化密切相关，相对于其他血脂因素更有意义。

Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid accumulation within the arterial wall. The imbalance between cholesterol influx and efflux, coupled with persistent inflammation, drives the progression of plaque formation. Lipophagy, a selective form of autophagy, specifically targets lipid droplets for lysosomal degradation. Consequently, this process is a notable regulator of cellular lipid homeostasis. In the present review, the core regulatory networks of lipophagy were systematically summarized, including the mechanistic target of rapamycin complex 1/AMP-activated protein kinase, transcription factor EB (TFEB) and farnesoid X receptor/cAMP response element-binding protein signaling axes. The multidimensional roles of lipophagy in key cell types involved in AS are also discussed. For example, in macrophages, lipophagy stabilizes plaques by promoting cholesterol efflux and inhibiting foam cell formation; however, dysregulated lipophagy can exacerbate necrotic core formation. In vascular smooth muscle cells, lipophagy regulates phenotype switching and calcification and in endothelial cells, lipophagy mitigates oxidative stress and inflammation. Advances in therapeutic strategies targeting lipophagy were evaluated, ranging from pharmacological agents (such as statins and metformin) to natural compounds (such as berberine and geniposide) and Traditional Chinese Medicine formulas. In conclusion, targeting lipophagy represents a pivotal therapeutic frontier for stabilizing atherosclerotic plaques; however, the broad application of autophagy inducers lacks precision. Future strategies should transition from generalized modulation to cell-type specific interventions that precisely calibrate the sirtuin 1-TFEB-lipophagy axis. Furthermore, elucidating the ‘double-edged’ role of lipophagy in late-stage plaque outcomes is required for developing safe, clinically translatable modulators.

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy mainly due to its extensive metastasis. Cancer-type organic anion transporting polypeptide 1B3 (Ct-OATP1B3), a newly discovered splice variant of solute carrier organic anion transporter family member 1B3 (SLCO1B3), has been reported to be overexpressed in several types of cancer. However, the biological function of Ct-OATP1B3 remains largely unknown. Here, we reveal that Ct-OATP1B3 is overexpressed in HGSOC and promotes the metastasis of HGSOC in vivo and in vitro. Mechanically, Ct-OATP1B3 directly interacts with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), an RNA-binding protein, which results in enhancement of the mRNA stability and expression of carnitine palmitoyltransferase 1A (CPT1A) and NADH:Ubiquinone Oxidoreductase Subunit A2 (NDUFA2), leading to increased mitochondrial fatty acid beta-oxidation (FAO) and oxidative phosphorylation (OXPHOS) activities. The increased FAO and OXPHOS activities further facilitate adenosine triphosphate (ATP) production and cellular lamellipodia formation, which is the initial step in the processes of tumor cell migration and invasion. Taken together, our study provides an insight into the function and underlying mechanism of Ct-OATP1B3 in HGSOC metastasis, and highlights Ct-OATP1B3 as a novel prognostic marker as well as therapeutic target in HGSOC.

In haematological malignancies, such as malignant lymphoma, reprogramming of fatty acid metabolism favours tumour cell survival and drug resistance. Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA), an enzyme involved in fatty acid beta-oxidation (FAO), is overexpressed in high-grade lymphoma and is a predictor of poor prognosis in diffuse large B-cell lymphoma (DLBCL). HADHB forms a heterodimer with HADHA and functions as an FAO enzyme together with HADHA; however, the relevance of its expression in malignant lymphoma is unknown. In this study, we investigated the roles and antitumour effects of HADHB expression in malignant lymphoma. Immunohistochemical analysis showed that HADHB was frequently overexpressed in the high-grade lymphoma subtype. HADHB overexpression was observed in 68% (87/128) of DLBCL cases and was an independent predictor of poor prognosis (p=0.001). In vitro analysis demonstrated that HADHB knockdown suppressed cell proliferation in LCL-K and MD901 cells (p<0.05). Additionally, treatment with the FAO inhibitor, ranolazine, increased cell death in control cells compared with that in HADHB knockdown LCL-K and MD901 cells (p<0.01). Cell death was also suppressed by the ferroptosis inhibitor, ferrosatin-1, in LCL-K and MD901 cells (p<0.05). Collectively, these findings provide basic evidence for the development of new cell death-based therapies for refractory malignant lymphoma. We plan to perform prospective studies and preclinical studies using animal models to confirm these results.

… and hence of glucose oxidation, by fatty acid oxidation, and by cyclic AMR This provides the major new theme in this paper. … X is an unidentified metabolite of the beta oxidation pathway …

It has been suggested that retinoic acid (RA) has a potential role in the prevention of atherosclerotic CVD. In the present study, we used J774A.1 cell lines and primary peritoneal macrophages to investigate the protective effects of RA on foam cell formation and atherogenesis in apoE-deficient (apoE− / −) mice. A total of twenty male apoE− / − mice (n 10 animals per group), aged 8 weeks, were fed on a high-fat diet (HFD) and treated with vehicle or 9-cis-RA for 8 weeks. The atherosclerotic plaque area in the aortic sinus of mice in the 9-cis-RA group was 40·7 % less than that of mice in the control group (P&lt; 0·01). Mouse peritoneal macrophages from the 9-cis-RA group had higher protein expression levels of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) than those from the control group. Serum total and LDL-cholesterol concentrations were lower in the 9-cis-RA group than in the control group (P&lt; 0·05). In vitro studies showed that incubation of cholesterol-loaded J774A.1 macrophages with 9-cis-RA (0·1, 1 and 10 μmol/l) induced cholesterol efflux in a dose-dependent manner. The 9-cis-RA treatment markedly attenuated lipid accumulation in macrophages exposed to oxidised LDL. Moreover, treatment with 9-cis-RA significantly increased the protein expression levels of ABCA1 and ABCG1 in J774A.1 macrophages in a dose-dependent manner. Furthermore, 9-cis-RA dose-dependently enhanced the protein expression level of liver X receptor-α (LXRα), the upstream regulator of ABCA1 and ABCG1. Taken together, the present results show that 9-cis-RA suppresses foam cell formation and prevents HFD-induced atherogenesis via the LXRα-dependent up-regulation of ABCA1 and ABCG1.

… Taken together, these data suggest that CTRP15 promotes cholesterol efflux from macrophages and subsequently ameliorates lipid accumulation and atherosclerosis. …

… macrophages, … efflux and increased cholesterol levels in THP-1 macrophage-derived foam cells. Our study demonstrates that puerarin promotes ABCA1-mediated cholesterol efflux and …

The capacity of macrophages to dispose of cholesterol deposited in the atherosclerotic plaque depends on their ability to activate cholesterol efflux pathways. To develop athero-protective therapies aimed at promoting macrophage cholesterol efflux, cholesterol metabolism in THP-1 monocyte-derived macrophages has been extensively studied, but the intrinsic sensitivity of monocytes and the lack of a standardized procedure to differentiate THP-1 monocytes into macrophages have made it difficult to utilize THP-1 macrophages in the same or similar degree of differentiation across studies. The variability has resulted in lack of understanding of how the differentiation affects cholesterol metabolism, and here we review and investigate the effects of THP-1 differentiation on cholesterol efflux. The degree of THP-1 differentiation was inversely associated with ATP binding cassette A1 (ABCA1) transporter-mediated cholesterol efflux. The differentiation-associated decrease in ABCA1-mediated cholesterol efflux occurred despite an increase in ABCA1 expression. In contrast, DSC1 expression decreased during the differentiation. DSC1 is a negative regulator of the ABCA1-mediated efflux pathway and a DSC1-targeting agent, docetaxel showed high potency and efficacy in promoting ABCA1-mediated cholesterol efflux in THP-1 macrophages. These data suggest that pharmacological targeting of DSC1 may be more effective than increasing ABCA1 expression in promoting macrophage cholesterol efflux. In summary, the comparison of THP-1 macrophage subtypes in varying degrees of differentiation provided new insights into cholesterol metabolism in macrophages and allowed us to identify a viable target DSC1 for the promotion of cholesterol efflux in differentiated macrophages. Docetaxel and other pharmacological strategies targeting DSC1 may hold significant potential for reducing atherogenic cholesterol deposition.

… The macrophage and its related cholesterol efflux are … reaction between lipid-loaded macrophages and lipid-acceptors … Recent studies have reported that an impaired cholesterol efflux …

… Since the scavenger receptor class A (SRA) is … clearance (t1/2 < 2 min versus > 5 h). The LCO-dA2dG10-induced liposome clearance was fully dependent on SRA, as the clearance …

… Liver scavenger receptor class B type I (SR-BI) exerts atheroprotective effects through selective lipid uptake (SLU) from high-density lipoprotein cholesterol (HDL-C). Low hepatic SR-BI …

… Several independent clones were isolated and all found to encode the scavenger receptor class B, type I (SR-BI), a protein suggested by others to play a role in cholesterol absorption. …

… leads to delayed HDL clearance and elevated HDL … lipid composition of the lipoproteins isolated by density gradient ultracentrifugation. There was no significant difference in the lipid …

… (CETPTg) mice with liver scavenger receptor BI (SR-BI) deficiency [ie, PDZK1 gene knockout (PDZK1O)], and with receptor associated protein (RAP) overexpression, to block LDL …