Which is the current knowledge on man-made endocrine- disrupting chemicals in follicular fluid? An overview of effects on ovarian function and reproductive health.

The increase in female reproductive disorders, such as polycystic ovary syndrome, endometriosis, and diminished ovarian reserve that lead to subfertility and infertility, has encouraged researchers to search and discover their underlying causes and risk factors. One of the crucial factors that may influence the increasing number of reproductive issues is environmental pollution, particularly exposure to man-made endocrine-disrupting chemicals (EDCs). EDCs can interfere with the ovarian microenvironment, impacting not only granulosa cell function but also other surrounding ovarian cells and follicular fluid (FF), which all play essential roles for oocyte development, maturation, and overall reproductive function. FF surrounds developing oocytes within an ovarian follicle and represents a dynamic milieu. EDCs are usually found in biological fluids, and FF is therefore of interest in this respect. This narrative review examines the current knowledge on specific classes of EDCs, including industrial chemicals, pesticides, and plasticizers, and their known effects on hormonal signaling pathways, gene expression, mitochondrial function, oxidative stress induction, and inflammation in FF. We describe the impact of EDCs on the development of reproductive disorders, oocyte quality, menstrual cycle regulation, and their effect on assisted reproductive technique outcomes. The potential transgenerational effects of EDCs on offspring through animal and first-human studies has been considered also. While significant progress has been made, the current understanding of EDCs' effects on ovarian function, particularly in humans, remains limited, underscoring the need for further research to clarify actions and effects of EDCs in the ovary.

Limited Alleviation of Lysosomal Acid Lipase Deficiency by Deletion of Matrix Metalloproteinase 12.

Lysosomal acid lipase (LAL) is the only known enzyme that degrades cholesteryl esters and triglycerides at an acidic pH. In LAL deficiency (LAL-D), dysregulated expression of matrix metalloproteinase 12 (MMP-12) has been described. The overexpression of MMP-12 in myeloid lineage cells causes an immune cell dysfunction resembling that of Lal knockout (Lal KO) mice. Both models develop progressive lymphocyte dysfunction and expansion of myeloid-derived suppressor (CD11b+ Gr-1+) cells. To study whether MMP-12 might be a detrimental contributor to the pathology of LAL-D, we have generated Lal/Mmp12 double knockout (DKO) mice. The phenotype of Lal/Mmp12 DKO mice closely resembled that of Lal KO mice, while the weight and morphology of the thymus were improved in Lal/Mmp12 DKO mice. Cytological examination of blood smears showed a mildly reversed lymphoid-to-myeloid shift in DKO mice. Despite significant decreases in CD11b+ Ly6G+ cells in the peripheral blood, bone marrow, and spleen of Lal/Mmp12 DKO mice, the hematopoietic bone marrow progenitor compartment and markers for neutrophil chemotaxis were unchanged. Since the overall severity of LAL-D remains unaffected by the deletion of Mmp12, we conclude that MMP-12 does not represent a viable target for treating the inflammatory pathology in LAL-D.

Behavioral and Neural Mechanisms Underlying Sensory-Motor Integration.

Sensory-motor integration represents a complex process requiring proper orchestration among multiple sources of sensory information to ensure the best task-related motor output [...].

Identification of regulatory networks and crosstalk factors in brown adipose tissue and liver of a cold-exposed cardiometabolic mouse model.

BACKGROUND: Activation of brown adipose tissue (BAT) has gained attention due to its ability to dissipate energy and counteract cardiometabolic diseases (CMDs). METHODS: This study investigated the consequences of cold exposure on the BAT and liver proteomes of an established CMD mouse model based on LDL receptor-deficient (LdlrKO) mice fed a high-fat, high-sucrose, high-cholesterol diet for 16 weeks. We analyzed energy metabolism in vivo and performed untargeted proteomics on BAT and liver of LdlrKO mice maintained at 22 °C or 5 °C for 7 days. RESULTS: We identified several dysregulated pathways, miRNAs, and transcription factors in BAT and liver of cold-exposed Ldlrko mice that have not been previously described in this context. Networks of regulatory interactions based on shared downstream targets and analysis of ligand-receptor pairs identified fibrinogen alpha chain (FGA) and fibronectin 1 (FN1) as potential crosstalk factors between BAT and liver in response to cold exposure. Importantly, genetic variations in the genes encoding FGA and FN1 have been associated with cardiometabolic-related phenotypes and traits in humans. DISCUSSION: This study describes the key factors, pathways, and regulatory networks involved in the crosstalk between BAT and the liver in a cold-exposed CMD mouse model. These findings may provide a basis for future studies aimed at testing whether molecular mediators, as well as regulatory and signaling mechanisms involved in tissue adaption upon cold exposure, could represent a target in cardiometabolic disorders.

Electrophysiological Correlates of Amplified Emotion-Related Cognitive Processing Evoked by Self-Administered Disgust Images.

In the processing of emotions, the brain prepares and reacts in distinctive manners depending upon the negative or positive nuance of the emotion elicitors. Previous investigations showed that negative elicitors generally evoke more intense neural activities than positive and neutral ones, as reflected in the augmented amplitude of all sub-components of the event-related potentials (ERP) late posterior positivity (LPP) complex, while less is known about the emotion of disgust. The present study aimed to examine whether the LPP complex during the processing of disgust stimuli showed greater amplitude than other emotion elicitors with negative or positive valences, thus confirming it as a neural marker of disgust-related negativity bias at earlier or later stages. Thus, in the present study, we leveraged the ERP technique during the execution of an affective self-administered visual stimuli task to disentangle the neural contributions associated with images of positive, negative, disgust, or neutral emotions. Crucially, we showed that handling with disgust elicitors prompted the greatest neural activity and the highest delay during self-administration. Overall, we demonstrated progressive neural activities associated with the unpleasantness of the emotion elicitors and peculiar processing for disgust compared with all other emotions.

Contextual expectations shape the motor coding of movement kinematics during the prediction of observed actions: A TMS study.

Contextual information may shape motor resonance and support intention understanding during observation of incomplete, ambiguous actions. It is unclear, however, whether this effect is contingent upon kinematics ambiguity or contextual information is continuously integrated with kinematics to predict the overarching action intention. Moreover, a differentiation between the motor mapping of the intention suggested by context or kinematics has not been clearly demonstrated. In a first action execution phase, 29 participants were asked to perform reaching-to-grasp movements towards big or small food objects with the intention to eat or to move; electromyography from the First Dorsal Interosseous (FDI) and Abductor Digiti Minimi (ADM) was recorded. Depending on object size, the intentions to eat or to move were differently implemented by a whole-hand or a precision grip kinematics, thus qualifying an action-muscle dissociation. Then, in a following action prediction task, the same participants were asked to observe an actor performing the same actions and to predict his/her intention while motor resonance was assessed for the same muscles. Of note, videos were interrupted at early or late action phases, and actions were embedded in contexts pointing toward an eating or a moving intention, congruently or incongruently with kinematics. We found greater involvement of the FDI or ADM in the execution of precision or whole-hand grips, respectively. Crucially, this pattern of activation was mirrored during observation of the same actions in congruent contexts, but it was cancelled out or reversed in the incongruent ones, either when videos were interrupted at either early or long phases of action deployment. Our results extend previous evidence by showing that contextual information shapes motor resonance not only under conditions of perceptual uncertainty but also when more informative kinematics is available.

Lipid-associated macrophages between aggravation and alleviation of metabolic diseases.

Lipid-associated macrophages (LAMs) are phagocytic cells with lipid-handling capacity identified in various metabolic derangements. During disease development, they locate to atherosclerotic plaques, adipose tissue (AT) of individuals with obesity, liver lesions in steatosis and steatohepatitis, and the intestinal lamina propria. LAMs can also emerge in the metabolically demanding microenvironment of certain tumors. In this review, we discuss major questions regarding LAM recruitment, differentiation, and self-renewal, and, ultimately, their acute and chronic functional impact on the development of metabolic diseases. Further studies need to clarify whether and under which circumstances LAMs drive disease progression or resolution and how their phenotype can be modulated to ameliorate metabolic disorders.

Cortical dynamics in visual areas induced by the first use of multifocal contact lenses in presbyopes.

A common non-spectacle strategy to correct presbyopia is to provide simultaneous images with multifocal optical designs. Understanding the neuroadaptation mechanisms behind multifocal devices usage would have important clinical implications, such as predicting whether patients will be able to tolerate multifocal optics. The aim of this study was to evaluate the brain correlates during the initial wear of multifocal contact lenses (CLs) using high-density visual evoked potential (VEP) measures. Fifteen presbyopes (mean age 51.8 ±â€¯2.6 years) who had previously not used multifocal CLs were enrolled. VEP measures were achieved while participants looked at arrays of 0.5 logMAR Sloan letters in three different optical conditions arranged with CLs: monofocal condition with the optical power appropriate for the distance viewing; multifocal correction with medium addition; and multifocal correction with low addition. An ANOVA for repeated measures showed that the amplitude of the C1 and N1 components significantly dropped with both multifocal low and medium addition CL conditions compared to monofocal CLs. The P1 and P2 components showed opposite behavior with an increase in amplitudes for multifocal compared to monofocal conditions. VEP data indicated that multifocal presbyopia corrections produce a loss of feedforward activity in the primary visual cortex that is compensated by extra feedback activity in extrastriate areas only, in both early and late visual processing.

Contextual Priors Shape Action Understanding before and beyond the Unfolding of Movement Kinematics.

Previous studies have shown that contextual information may aid in guessing the intention underlying others' actions in conditions of perceptual ambiguity. Here, we aimed to evaluate the temporal deployment of contextual influence on action prediction with increasing availability of kinematic information during the observation of ongoing actions. We used action videos depicting an actor grasping an object placed on a container to perform individual or interpersonal actions featuring different kinematic profiles. Crucially, the container could be of different colors. First, in a familiarization phase, the probability of co-occurrence between each action kinematics and color cues was implicitly manipulated to 80% and 20%, thus generating contextual priors. Then, in a testing phase, participants were asked to predict action outcome when the same action videos were occluded at five different timeframes of the entire movement, ranging from when the actor was still to when the grasp of the object was fully accomplished. In this phase, all possible action-contextual cues' associations were equally presented. The results showed that for all occlusion intervals, action prediction was more facilitated when action kinematics deployed in high- than low-probability contextual scenarios. Importantly, contextual priors shaped action prediction even in the latest occlusion intervals, where the kinematic cues clearly unveiled an action outcome that was previously associated with low-probability scenarios. These residual contextual effects were stronger in individuals with higher subclinical autistic traits. Our findings highlight the relative contribution of kinematic and contextual information to action understanding and provide evidence in favor of their continuous integration during action observation.

Regional Differences in the Small Intestinal Proteome of Control Mice and of Mice Lacking Lysosomal Acid Lipase.

The metabolic contribution of the small intestine (SI) is still unclear despite recent studies investigating the involvement of single cells in regional differences. Using untargeted proteomics, we identified regional characteristics of the three intestinal tracts of C57BL/6J mice and found that proteins abundant in the mouse ileum correlated with the high ileal expression of the corresponding genes in humans. In the SI of C57BL/6J mice, we also detected an increasing abundance of lysosomal acid lipase (LAL), which is responsible for degrading triacylglycerols and cholesteryl esters within the lysosome. LAL deficiency in patients and mice leads to lipid accumulation, gastrointestinal disturbances, and malabsorption. We previously demonstrated that macrophages massively infiltrated the SI of Lal-deficient (KO) mice, especially in the duodenum. Using untargeted proteomics (ProteomeXchange repository, data identifier PXD048378), we revealed a general inflammatory response and a common lipid-associated macrophage phenotype in all three intestinal segments of Lal KO mice, accompanied by a higher expression of GPNMB and concentrations of circulating sTREM2. However, only duodenal macrophages activated a metabolic switch from lipids to other pathways, which were downregulated in the jejunum and ileum of Lal KO mice. Our results provide new insights into the process of absorption in control mice and possible novel markers of LAL-D and/or systemic inflammation in LAL-D.

Effect of anticipatory multisensory integration on sensory-motor performance.

Multisensory integration (MSI) is a phenomenon that occurs in sensory areas after the presentation of multimodal stimuli. Nowadays, little is known about the anticipatory top-down processes taking place in the preparation stage of processing before the stimulus onset. Considering that the top-down modulation of modality-specific inputs might affect the MSI process, this study attempts to understand whether the direct modulation of the MSI process, beyond the well-known sensory effects, may lead to additional changes in multisensory processing also in non-sensory areas (i.e., those related to task preparation and anticipation). To this aim, event-related potentials (ERPs) were analyzed both before and after auditory and visual unisensory and multisensory stimuli during a discriminative response task (Go/No-go type). Results showed that MSI did not affect motor preparation in premotor areas, while cognitive preparation in the prefrontal cortex was increased and correlated with response accuracy. Early post-stimulus ERP activities were also affected by MSI and correlated with response time. Collectively, the present results point to the plasticity accommodating nature of the MSI processes, which are not limited to perception and extend to anticipatory cognitive preparation for task execution. Further, the enhanced cognitive control emerging during MSI is discussed in the context of Bayesian accounts of augmented predictive processing related to increased perceptual uncertainty.

Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice.

OBJECTIVE: Lysosomal acid lipase (LAL) is the only enzyme known to hydrolyze cholesteryl esters (CE) and triacylglycerols in lysosomes at an acidic pH. Despite the importance of lysosomal hydrolysis in skeletal muscle (SM), research in this area is limited. We hypothesized that LAL may play an important role in SM development, function, and metabolism as a result of lipid and/or carbohydrate metabolism disruptions. RESULTS: Mice with systemic LAL deficiency (Lal-/-) had markedly lower SM mass, cross-sectional area, and Feret diameter despite unchanged proteolysis or protein synthesis markers in all SM examined. In addition, Lal-/- SM showed increased total cholesterol and CE concentrations, especially during fasting and maturation. Regardless of increased glucose uptake, expression of the slow oxidative fiber marker MYH7 was markedly increased in Lal-/-SM, indicating a fiber switch from glycolytic, fast-twitch fibers to oxidative, slow-twitch fibers. Proteomic analysis of the oxidative and glycolytic parts of the SM confirmed the transition between fast- and slow-twitch fibers, consistent with the decreased Lal-/- muscle size due to the "fiber paradox". Decreased oxidative capacity and ATP concentration were associated with reduced mitochondrial function of Lal-/- SM, particularly affecting oxidative phosphorylation, despite unchanged structure and number of mitochondria. Impairment in muscle function was reflected by increased exhaustion in the treadmill peak effort test in vivo. CONCLUSION: We conclude that whole-body loss of LAL is associated with a profound remodeling of the muscular phenotype, manifested by fiber type switch and a decline in muscle mass, most likely due to dysfunctional mitochondria and impaired energy metabolism, at least in mice.

Glycoprotein Non-Metastatic Protein B (GPNMB): The Missing Link Between Lysosomes and Obesity.

As a result of an unhealthy diet and limited physical activity, obesity has become a widespread pandemic worldwide and is an important predictor for the development of cardiovascular disease. Obesity is often characterized by a pro-inflammatory environment in white adipose tissue (WAT), mainly due to increased macrophage infiltration. These immune cells boost their lipid concentrations by accumulating the content of dying adipocytes. As the lysosome is highly involved in lipid handling, the progressive lipid accumulation may result in lysosomal stress and a metabolic shift. Recent studies have identified glycoprotein non-metastatic melanoma protein B (GPNMB) as a novel marker of inflammatory diseases. GPNMB is a type I transmembrane protein on the cell surface of various cell types, such as macrophages, dendritic cells, osteoblasts, and microglia, from which it can be proteolytically cleaved into a soluble molecule. It is induced by lysosomal stress via microphthalmia-associated transcription factor and thus has been found to be upregulated in many lysosomal storage disorders. In addition, a clear connection between GPNMB and obesity was recently established. GPNMB was shown to have protective and anti-inflammatory effects in most cases, preventing the progression of obesity-related metabolic disorders. In contrast, soluble GPNMB likely has the opposite effect and promotes lipogenesis in WAT. This review aims to summarize and clarify the role of GPNMB in the progression of obesity and to highlight its potential use as a biomarker for lipid-associated disorders.

Temporal spectral evolution of pre-stimulus brain activity in visual and visuomotor tasks.

The aim of this study was to describe the spectral features of pre-stimulus event-related potential (ERP) components elicited in visual tasks such as the Bereitschaftspotential (BP), prefrontal negativity (pN) and visual negativity (vN). ERPs are considered time-locked and phase-locked (evoked) activity, but we have also analyzed the non-phase but time-locked (induced) activity in the same interval by applying the temporal spectral evolution (TSE) method. Participants (N = 26) were tested in a passive task, a simple response task (SRT) and a discriminative response task (DRT), where EEG activity was recorded with 64 scalp electrodes. We analyzed the time-frequency modulations (phase and non-phase) prior to the onset of the stimuli in the sub-delta, delta, theta, alpha, beta, and gamma frequency bands. The results showed that all the pre-stimulus ERP components were mainly regulated by evoked activity in the sub-delta band. On the other hand, induced activity seems to be linked to evoked responses but with a different psychophysiological role. We concluded that other preparatory cognitive mechanisms associated with ERPs can also be detected by the TSE method. This finding may suggest underlying mechanisms in non-phase activity and requires the addition of non-phase activity analysis to the traditional analysis (phase and evoked activity).

Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice.

BACKGROUND: Matrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear. METHODS: We investigated the impact of MMP12 deficiency on CMDs in a mouse model that mimics human disease by simultaneously developing adipose tissue inflammation, insulin resistance, and atherosclerosis. To this end, we generated and characterized low-density lipoprotein receptor (Ldlr)/Mmp12-double knockout (DKO) mice fed a high-fat sucrose- and cholesterol-enriched diet for 16-20 weeks. RESULTS: DKO mice showed lower cholesterol and plasma glucose concentrations and improved insulin sensitivity compared with LdlrKO mice. Untargeted proteomic analyses of epididymal white adipose tissue revealed that inflammation- and fibrosis-related pathways were downregulated in DKO mice. In addition, genetic deletion of MMP12 led to alterations in immune cell composition and a reduction in plasma monocyte chemoattractant protein-1 in peripheral blood which indicated decreased low-grade systemic inflammation. Aortic en face analyses and staining of aortic valve sections demonstrated reduced atherosclerotic plaque size and collagen content, which was paralleled by an improved relaxation pattern and endothelial function of the aortic rings and more elastic aortic sections in DKO compared to LdlrKO mice. Shotgun proteomics revealed upregulation of anti-inflammatory and atheroprotective markers in the aortas of DKO mice, further supporting our data. In humans, MMP12 serum concentrations were only weakly associated with clinical and laboratory indicators of CMDs. CONCLUSION: We conclude that the genetic deletion of MMP12 ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, biomechanical properties of the aorta, and the development of atherosclerosis. Therefore, therapeutic strategies targeting MMP12 may represent a promising approach to combat CMDs.

Specific effect of a cognitive-motor dual-task training on sport performance and brain processing associated with decision-making in semi-elite basketball players.

OBJECTIVES: In this study, we aimed at evaluating the effects of cognitive-motor dual-task training (CMDT) on sport-specific athletic performance and cognitive functions of semi-elite basketball players. Further, we investigated the CMDT effects on reactive brain processing by employing event-related potential (ERP) analysis. DESIGN: A randomized controlled trial was conducted including 52 young semi-elite basketball players (28 females mean age 16.3 ± 1.1 years) who were randomly assigned into an experimental (Exp) group executing the CMDT and a control (Con) group performing standard motor training. METHOD: Athletes' sport-specific performance was evaluated with dribbling tests before and after a five-week training. Cognitive performance was assessed by measuring speed and accuracy in a discrimination response task. Brain activity associated with sensory processing, selective attention, and decision-making was measured through the P1, N1, and P3 components. The CMDT consisted of simultaneous execution of dribbling exercises and cognitive tasks which were realized using interactive devices located around the athlete on the basket court. Data were submitted to a mixed analysis of variance. RESULTS: Both groups showed some improvements from pre-to post-tests, but the Exp group improved basket-specific performance by 13% more than the Con group; in addition, the cognitive performance also improved more in the Exp group (25.8% in accuracy and 5.4% response speed). According to the EEG results, training did not affect sensory processing and attentional processing which were equally increased after both kinds of training; however, decision-making processes were specifically affected by the experimental training. CONCLUSIONS: This study confirmed the effectiveness of the proposed CMDT protocol on both sport-specific and cognitive performance of basketball players and showed that the neural basis of these benefits may be mediated by more intense decisional processing allowing faster connection between sensory encoding and response execution.

Brain dynamics of visual anticipation during spatial occlusion tasks in expert tennis players.

Stimulus identification and action outcome understanding for a rapid and accurate response selection, play a fundamental role in racquet sports. Here, we investigated the neurodynamics of visual anticipation in tennis manipulating the postural and kinematic information associated with the body of opponents by means of a spatial occlusion protocol. Event Related Potentials (ERPs) were evaluated in two groups of professional tennis players (N = 37) with different levels of expertise, while they observed pictures of opponents and predicted the landing position as fast and accurately as possible. The observed action was manipulated by deleting different body districts of the opponent (legs, ball, racket and arm, trunk). Full body image (no occlusion) was used as control condition. The worst accuracy and the slowest response time were observed in the occlusion of trunk and ball. The former was associated with a reduced amplitude of the ERP components likely linked to body processing (the N1 in the right hemisphere) and visual-motor integration awareness (the pP1), as well as with an increase of the late frontal negativity (the pN2), possibly reflecting an effort by the insula to recover and/or complete the most correct sensory-motor representation. In both occlusions, a decrease in the pP2 may reflect an impairment of decisional processes upon action execution following sensory evidence accumulation. Enhanced amplitude of the P3 and the pN2 components were found in more experienced players, suggesting a greater allocation of resources in the process connecting sensory encoding and response execution, and sensory-motor representation.

Top-down reconfiguration of SMA cortical connectivity during action preparation.

The Bereitschaftspotential (BP), a scalp potential recorded in humans during action preparation, is characterized by a slow amplitude increase over fronto-central regions as action execution approaches. We recorded TMS evoked-potentials (TEP) stimulating the supplementary motor area (SMA) at different time-points during a Go/No-Go task to assess whether and how cortical excitability and connectivity of this region change as the BP increases. When approaching BP peak, left SMA reactivity resulted greater. Concurrently, its effective connectivity increased with the left occipital areas, while it decreased with the right inferior frontal gyrus, indicating a fast reconfiguration of cortical networks during the preparation of the forthcoming action. Functional connectivity patterns supported these findings, suggesting a critical role of frequency-specific inter-areal interactions in implementing top-down mechanisms in the sensorimotor system prior to action. These findings reveal that BP time-course reflects quantitative and qualitative changes in SMA communication patterns that shape mechanisms involved in motor readiness.

Time Course of Reactive Brain Activities during a Stroop Color-Word Task: Evidence of Specific Facilitation and Interference Effects.

The Stroop test represents a widely used task in basic and clinical research for approaching the cognitive system functioning in humans. However, a clear overview of the neurophysiological signatures associated with the different sub-domains of this task remains controversial. In the present study, we leveraged the EEG technique to explore the modulation of specific post-stimulus ERPs components during the Stroop test. Critically, to better disentangle the contribution of facilitation (i.e., faster color identification times for color-congruent Stroop words) and interference (i.e., longer color identification times for color-incongruent Stroop words) processes prompted by the Stroop test, we delivered congruent and incongruent trials in two separate experimental blocks, each including the respective neutral condition. Thanks to this methodological manipulation, we were able to clearly dissociate the two sub-processes. Electrophysiological results suggest specific markers of brain activity for the facilitation and the interference effects. Indeed, distinctive Stroop-related ERPs (i.e., the P3, the N450, and the LPC) were differently modulated in the two sub-processes. Collectively, we provide evidence of selected brain activities involved in the reactive stage of processing associated with the Stroop effect.

Impact of (intestinal) LAL deficiency on lipid metabolism and macrophage infiltration.

OBJECTIVE: To date, the only enzyme known to be responsible for the hydrolysis of cholesteryl esters and triacylglycerols in the lysosome at acidic pH is lysosomal acid lipase (LAL). Lipid malabsorption in the small intestine (SI), accompanied by macrophage infiltration, is one of the most common pathological features of LAL deficiency. However, the exact role of LAL in intestinal lipid metabolism is still unknown. METHODS: We collected three parts of the SI (duodenum, jejunum, ileum) from mice with a global (LAL KO) or intestine-specific deletion of LAL (iLAL KO) and corresponding controls. RESULTS: We observed infiltration of lipid-associated macrophages into the lamina propria, where neutral lipids accumulate massively in the SI of LAL KO mice. In addition, LAL KO mice absorb less dietary lipids but have accelerated basolateral lipid uptake, secrete fewer chylomicrons, and have increased fecal lipid loss. Inflammatory markers and genes involved in lipid metabolism were overexpressed in the duodenum of old but not in younger LAL KO mice. Despite the significant reduction of LAL activity in enterocytes of enterocyte-specific (iLAL) KO mice, villous morphology, intestinal lipid concentrations, expression of lipid transporters and inflammatory genes, as well as lipoprotein secretion were comparable to control mice. CONCLUSIONS: We conclude that loss of LAL only in enterocytes is insufficient to cause lipid deposition in the SI, suggesting that infiltrating macrophages are the key players in this process.