Search Results (8)

Phospholipid transfer protein (PLTP) is a lipid transfer protein classically studied in the context of plasma lipoprotein metabolism, high-density lipoprotein (HDL) remodeling, and cardiovascular disease risk. PLTP facilitates phospholipid transfer between lipoproteins and regulates HDL particle size and composition through interactions with apolipoprotein A-I and apolipoprotein A-II. While its systemic roles in cholesterol handling, reverse cholesterol transport, and inflammatory signaling are well established, the cell-autonomous functions of PLTP within cardiomyocytes remain poorly defined, particularly in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Extensive experimental and clinical studies demonstrate that PLTP enhances ABCA1-dependent cholesterol efflux primarily by stabilizing ABCA1 at the plasma membrane and by promoting the generation of lipid-poor apolipoprotein A-I and pre-β HDL particles, which serve as efficient cholesterol acceptors; the magnitude of these effects depends on cellular context, PLTP expression levels, and the availability of lipid acceptors. PLTP expression is metabolically regulated and widely distributed across tissues, including macrophages and other non-hepatic cells, supporting roles beyond circulating lipoprotein remodeling. Altered PLTP activity has been linked to atherosclerosis, cardiovascular disease, and inflammatory pathways, underscoring its relevance to cardiac pathophysiology. Emerging evidence further suggests that intracellular cholesterol distribution, rather than total cholesterol content alone, critically influences mitochondrial membrane composition, bioenergetics, and stress signaling in cardiomyocytes. These observations raise the possibility that PLTP-regulated lipid flux may indirectly shape mitochondrial function by modulating cellular cholesterol homeostasis. This review synthesizes current knowledge of PLTP biology, cholesterol metabolism, and lipoprotein remodeling, and integrates these concepts with emerging frameworks in cardiomyocyte lipid metabolism and mitochondrial physiology. We highlight human iPSC-derived cardiomyocytes as a strategic and translationally relevant platform to investigate PLTP’s non-canonical, cell-intrinsic roles, identify critical knowledge gaps, and propose future directions for elucidating how PLTP may influence mitochondrial function in human cardiac cells. Full article

Bioenergetic membranes of mitochondria, thylakoids, and chromatophores are primary sites of ATP production in living cells. These membranes contain an electron transport chain (ETC) in which electrons are shuttled between a series of redox proteins during the generation of ATP via oxidative phosphorylation. The phospholipid composition of these membranes, which often include negative lipids, plays a role in determining the electrostatics of their surface owing to the spatial distribution of their charged head groups. Cardiolipin (CDL) is a phospholipid commonly associated with bioenergetic membranes and is also a significant contributor to the negative surface charge. Interactions between cytochromes and phospholipid head groups in the membrane can in principle affect the rate of its travel between ETC components, hence influencing the rate of ATP turnover. Here, we use molecular dynamic (MD) simulations that feature an accelerated membrane model, termed highly mobile membrane mimetic (HMMM), to study protein–lipid interactions during the diffusion of cytochrome c₂ between redox partners in a bioenergetic membrane. We observe a “skipping” mode of diffusion for cytochromes along with a bias for binding to anionic lipids, particularly with a strong preference for CDL. During diffusion, cytochrome c₂ maintains a relatively fixed tilt with respect to the membrane normal with wider fluctuations in its angle with respect to the plane of the membrane. The obtained results describing the behavior of cytochrome c₂ on a representative bioenergetic membrane have direct ramifications in shuttling motions of other similar electron-carrying elements in other bioenergetic membranes, which are composed of a significant amount of anionic lipids. The mode of surface-restricted diffusion reported here would modulate rapid electron transfer between the ETC complexes anchored in bioenergetic membranes by reducing the search space between them. Full article

Other than representing the main source of nutrition for newborn mammals, milk delivers a sophisticated signaling system from mother to child that promotes postnatal health. The bioactive components transferred through the milk intake are important for the development of the newborn immune system and include oligosaccharides, lactoferrin, lysozyme, α-La, and immunoglobulins. In the last 15 years, a pivotal role in this mother-to-child exchange has been attributed to extracellular vesicles (EVs). EVs are micro- and nanosized structures enclosed in a phospholipidic double-layer membrane that are produced by all cell types and released in the extracellular environment, reaching both close and distant cells. EVs mediate the intercellular cross-talk from the producing to the receiving cell through the transfer of molecules contained within them such as proteins, antigens, lipids, metabolites, RNAs, and DNA fragments. The complex cargo can induce a wide range of functional modulations in the recipient cell (i.e., anti-inflammatory, immunomodulating, angiogenetic, and pro-regenerative modulations) depending on the type of producing cells and the stimuli that these cells receive. EVs can be recovered from every biological fluid, including blood, urine, bronchoalveolar lavage fluid, saliva, bile, and milk, which is one of the most promising scalable vesicle sources. This review aimed to present the state-of-the-art of animal-milk-derived EV (mEV) studies due to the exponential growth of this field. A focus on the beneficial potentialities for human health and the issues of studying vesicles from milk, particularly for the analytical methodologies applied, is reported. Full article

Bacterial lipopolysaccharides (LPS, endotoxins) are found in high amounts in the gut lumen. LPS can cross the gut barrier and pass into the blood (endotoxemia), leading to low-grade inflammation, a common scheme in metabolic diseases. Phospholipid transfer protein (PLTP) can transfer circulating LPS to plasma lipoproteins, thereby promoting its detoxification. However, the impact of PLTP on the metabolic fate and biological effects of gut-derived LPS is unknown. This study aimed to investigate the influence of PLTP on low-grade inflammation, obesity and insulin resistance in relationship with LPS intestinal translocation and metabolic endotoxemia. Wild-type (WT) mice were compared with Pltp-deficient mice (Pltp-KO) after a 4-month high-fat (HF) diet or oral administration of labeled LPS. On a HF diet, Pltp-KO mice showed increased weight gain, adiposity, insulin resistance, lipid abnormalities and inflammation, together with a higher exposure to endotoxemia compared to WT mice. After oral administration of LPS, PLTP deficiency led to increased intestinal translocation and decreased association of LPS to lipoproteins, together with an altered catabolism of triglyceride-rich lipoproteins (TRL). Our results show that PLTP, by modulating the intestinal translocation of LPS and plasma processing of TRL-bound LPS, has a major impact on low-grade inflammation and the onset of diet-induced metabolic disorders. Full article

Phospholipids are the basic structure block of eukaryotic membranes, in both the outer and inner membranes, which delimit cell organelles. Phospholipids can also be damaged by oxidative stress produced by mitochondria, for instance, becoming oxidized phospholipids. These damaged phospholipids have been related to prevalent diseases such as atherosclerosis or non-alcoholic steatohepatitis (NASH) because they alter gene expression and induce cellular stress and apoptosis. One of the main sites of phospholipid synthesis is the endoplasmic reticulum (ER). ER association with other organelles through membrane contact sites (MCS) provides a close apposition for lipid transport. Additionally, an important advance in this small cytosolic gap are lipid transfer proteins (LTPs), which accelerate and modulate the distribution of phospholipids in other organelles. In this regard, LTPs can be established as an essential point within phospholipid circulation, as relevant data show impaired phospholipid transport when LTPs are defected. This review will focus on phospholipid function, metabolism, non-vesicular transport, and associated diseases. Full article

Among the phospholipase A₂ (PLA₂) superfamily, the secreted PLA₂ (sPLA₂) family contains 11 mammalian isoforms that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using sPLA₂-deficient or -overexpressed mouse strains, along with mass spectrometric lipidomics to determine sPLA₂-driven lipid pathways, have revealed the diverse pathophysiological roles of sPLA₂s in various biological events. In general, individual sPLA₂s exert their specific functions within tissue microenvironments, where they are intrinsically expressed through hydrolysis of extracellular phospholipids. Recent studies have uncovered a new aspect of group IIA sPLA₂ (sPLA₂-IIA), a prototypic sPLA₂ with the oldest research history among the mammalian PLA₂s, as a modulator of the gut microbiota. In the intestine, Paneth cell-derived sPLA₂-IIA acts as an antimicrobial protein to shape the gut microbiota, thereby secondarily affecting inflammation, allergy, and cancer in proximal and distal tissues. Knockout of intestinal sPLA₂-IIA in BALB/c mice leads to alterations in skin cancer, psoriasis, and anaphylaxis, while overexpression of sPLA₂-IIA in Pla2g2a-null C57BL/6 mice induces systemic inflammation and exacerbates arthritis. These phenotypes are associated with notable changes in gut microbiota and fecal metabolites, are variable in different animal facilities, and are abrogated after antibiotic treatment, co-housing, or fecal transfer. These studies open a new mechanistic action of this old sPLA₂ and add the sPLA₂ family to the growing list of endogenous factors capable of affecting the microbe–host interaction and thereby systemic homeostasis and diseases. Full article

Liver X receptors (LXRs) play a pivotal role in fatty acid (FA) metabolism. So far, the lipogenic consequences of in vivo LXR activation, as characterized by a major hepatic steatosis, has constituted a limitation to the clinical development of pharmacological LXR agonists. However, recent studies provided a different perspective. Beyond the quantitative accumulation of FA, it appears that LXRs induce qualitative changes in the FA profile and in the distribution of FAs among cellular lipid species. Thus, LXRs activate the production of polyunsaturated fatty acids (PUFAs) and their distribution into phospholipids via the control of FA desaturases, FA elongases, lysophosphatidylcholine acyltransferase (LPCAT3), and phospholipid transfer protein (PLTP). Therefore, LXRs control, in a dynamic manner, the PUFA composition and the physicochemical properties of cell membranes as well as the release of PUFA-derived lipid mediators. Recent studies suggest that modulation of PUFA and phospholipid metabolism by LXRs are involved in the control of lipogenesis and lipoprotein secretion by the liver. In myeloid cells, the interplay between LXR and PUFA metabolism affects the inflammatory response. Revisiting the complex role of LXRs in FA metabolism may open new opportunities for the development of LXR modulators in the field of cardiometabolic diseases. Full article

The spatiotemporal regulation of calcium (Ca²⁺) storage in late endosomes (LE) and lysosomes (Lys) is increasingly recognized to influence a variety of membrane trafficking events, including endocytosis, exocytosis, and autophagy. Alterations in Ca²⁺ homeostasis within the LE/Lys compartment are implicated in human diseases, ranging from lysosomal storage diseases (LSDs) to neurodegeneration and cancer, and they correlate with changes in the membrane binding behaviour of Ca²⁺-binding proteins. This also includes Annexins (AnxA), which is a family of Ca²⁺-binding proteins participating in membrane traffic and tethering, microdomain organization, cytoskeleton interactions, Ca²⁺ signalling, and LE/Lys positioning. Although our knowledge regarding the way Annexins contribute to LE/Lys functions is still incomplete, recruitment of Annexins to LE/Lys is greatly influenced by the availability of Annexin bindings sites, including acidic phospholipids, such as phosphatidylserine (PS) and phosphatidic acid (PA), cholesterol, and phosphatidylinositol (4,5)-bisphosphate (PIP2). Moreover, the cytosolic portion of LE/Lys membrane proteins may also, directly or indirectly, determine the recruitment of Annexins to LE. Strikingly, within LE/Lys, AnxA1, A2, A6, and A8 differentially contribute to cholesterol transport along the endocytic route, in particular, cholesterol transfer between LE and other compartments, positioning Annexins at the centre of major pathways mediating cellular cholesterol homeostasis. Underlying mechanisms include the formation of membrane contact sites (MCS) and intraluminal vesicles (ILV), as well as the modulation of LE-cholesterol transporter activity. In this review, we will summarize the current understanding how Annexins contribute to influence LE/Lys membrane transport and associated functions. Full article