Explore the vast range of titles available.

Key Points This Review focuses on the pathways that catabolize cellular triacylglycerol ('fat'), namely, neutral lipolysis, acid lipolysis and lipophagy. Neutral lipolysis of triglycerides in cytosolic lipid droplets relies on three lipid hydrolases (lipases): adipose triglyceride lipase, hormone-sensitive lipase and monoacylglycerol lipase. The consecutive action of these enzymes provides free fatty acids and glycerol for energy production and other metabolic pathways during fasting. The regulation of neutral lipolysis is complex and involves numerous proteins, hormones, growth factors and cytokines. Conversely, products and intermediates of neutral lipolysis regulate key metabolic pathways by transcriptional and post-transcriptional mechanisms. Lipophagy is a subtype of macroautophagy. Portions of cytosolic lipid droplets are engulfed by lipoautophagosomes and transported to lysosomes, where triacylglycerols and other lipids undergo acid lipolysis by lysosomal acid lipase. The regulation of acid lipolysis is less complex than the regulation of neutral lipolysis, but again, the products and intermediates of triacylglycerol hydrolysis exit lysosomes and regulate multiple key processes in energy metabolism. Neutral lipolysis, acid lipolysis and lipophagy cooperate mechanistically. Rare mutations in the genes coding for adipose triglyceride lipase; its co-activator, lipid droplet-binding protein CGI-58; hormone-sensitive lipase; and lysosomal acid lipase cause distinct metabolic disorders in humans. Recent insights led to a better understanding of how cellular triacylglycerol catabolism affects the pathogenesis of metabolic diseases, cancer and cancer-associated cachexia and highlighted potential treatment strategies for lipid-associated disorders. Lipolysis degrades triacylglycerols to supply cells with free fatty acids, which are essential components of membrane lipids and substrates for energy production. Recent discoveries transformed our understanding of the functions of and crosstalk between 'neutral' lipolysis, which occurs in the cytosol, and lipophagy and 'acid' lipolysis, which occur in lysosomes, and how dysfunction in these processes contributes to metabolic diseases. Fatty acids are the most efficient substrates for energy production in vertebrates and are essential components of the lipids that form biological membranes. Synthesis of triacylglycerols from non-esterified free fatty acids (FFAs) combined with triacylglycerol storage represents a highly efficient strategy to stockpile FFAs in cells and prevent FFA-induced lipotoxicity. Although essentially all vertebrate cells have some capacity to store and utilize triacylglycerols, white adipose tissue is by far the largest triacylglycerol depot and is uniquely able to supply FFAs to other tissues. The release of FFAs from triacylglycerols requires their enzymatic hydrolysis by a process called lipolysis. Recent discoveries thoroughly altered and extended our understanding of lipolysis. This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid' lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases. Answers to these questions will likely uncover novel strategies for the treatment of prevalent metabolic diseases.

Obesity increases the risk for a number of diseases including cardiovascular diseases and type 2 diabetes. Excess saturated fatty acids (SFAs) in obesity play a significant role in cardiovascular diseases by activating innate immunity responses. However, the mechanisms by which SFAs activate the innate immune system are not fully known. Here we report that palmitic acid (PA), the most abundant circulating SFA, induces myocardial inflammatory injury through the Toll-like receptor 4 (TLR4) accessory protein MD2 in mouse and cell culture experimental models. Md2 knockout mice are protected against PA- and high-fat diet-induced myocardial injury. Studies of cell surface binding, cell-free protein–protein interactions and molecular docking simulations indicate that PA directly binds to MD2, supporting a mechanism by which PA activates TLR4 and downstream inflammatory responses. We conclude that PA is a crucial contributor to obesity-associated myocardial injury, which is likely regulated via its direct binding to MD2. The free fatty acid-mediated inflammatory activities are regulated through TLR4. Here the authors show that palmitic acid binds to MD2, initiating complex formation with TLR4, recruitment of MyD88, and subsequent activation of pro-inflammatory molecules, and that MD2 blockade protects against diet-induced cardiac dysfunction.

The thermogenic activity of brown adipose tissue (BAT) and browning of white adipose tissue are important components of energy expenditure. Here we show that GPR120, a receptor for polyunsaturated fatty acids, promotes brown fat activation. Using RNA-seq to analyse mouse BAT transcriptome, we find that the gene encoding GPR120 is induced by thermogenic activation. We further show that GPR120 activation induces BAT activity and promotes the browning of white fat in mice, whereas GRP120-null mice show impaired cold-induced browning. Omega-3 polyunsaturated fatty acids induce brown and beige adipocyte differentiation and thermogenic activation, and these effects require GPR120. GPR120 activation induces the release of fibroblast growth factor-21 (FGF21) by brown and beige adipocytes, and increases blood FGF21 levels. The effects of GPR120 activation on BAT activation and browning are impaired in FGF21-null mice and cells. Thus, the lipid sensor GPR120 activates brown fat via a mechanism that involves induction of FGF21. GPR120 is a G-protein-coupled receptor that binds polyunsaturated fatty acids. Here, the authors show that GPR120 is upregulated in brown fat in cold-exposed mice, and mediates thermogenic activation of brown fat via a mechanism that, at least in part, depends on the release of the adipokine FGF21.

Metabolic distribution of fatty acid to organelles is an essential biological process for energy homeostasis as well as for the maintenance of membrane integrity, and the metabolic pathways are strictly regulated in response to environmental stimuli. Herein, we report a fluorescent fatty acid probe, which bears an azapyrene dye that changes its absorption and emission features depending on the microenvironment polarity of the organelle into which it is transported. Owing to the environmental sensitivity of this dye, the distribution of the metabolically incorporated probe in non-polar lipid droplets, medium-polarity membranes, and the polar aqueous regions, can be visualized in different colors. Based on density scatter plots of the fluorophore, we demonstrate that the degradation of triacylglycerols in lipid droplets occurs predominantly via lipolysis rather than lipophagy in nutrition-starved hepatocytes. This tool can thus be expected to significantly advance our understanding of the lipid metabolism in living organisms. Metabolic distribution of fatty acids to organelles is an essential biological process for energy homeostasis. Here the authors report a fluorescent probe that allows multicolour visualisation of the intracellular distribution of exogenous fatty acids, metabolically incorporated as lipid components.

Previous studies have shown that each edible oil type has its own characteristic fatty acid profile; however, no method has yet been described allowing the identification of oil types simply based on this characteristic. Moreover, the fatty acid profile of a specific oil type can be mimicked by a mixture of 2 or more oil types. This has led to fraudulent oil adulteration and intentional mislabeling of edible oils threatening food safety and endangering public health. Here, we present a machine learning method to uncover fatty acid patterns discriminative for ten different plant oil types and their intra-variability. We also describe a supervised end-to-end learning method that can be generalized to oil composition of any given mixtures. Trained on a large number of simulated oil mixtures, independent test dataset validation demonstrates that the model has a 50 th percentile absolute error between 1.4–1.8% and a 90 th percentile error of 4–5.4% for any 3-way mixtures of the ten oil types. The deep learning model can also be further refined with on-line training. Because oil-producing plants have diverse geographical origins and hence slightly varying fatty acid profiles, an online-training method provides also a way to capture useful knowledge presently unavailable. Our method allows the ability to control product quality, determining the fair price of purchased oils and in-turn allowing health-conscious consumers the future of accurate labeling. Fraudulent adulteration of edible oils is based on the fact that their characteristic fatty acid profile can be mimicked with mixtures of other oil types. Here, the authors use a deep learning method to uncover fatty acid patterns discriminative for ten different plant oil types and to discern composition of mixtures.

Although previous studies have indicated important roles of palmitate, a saturated fatty acid, in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), it remains unclear how palmitate contributes to inflammation and fibrosis in the liver. Administration of palmitate in high fat diet (HFD)-fed but not basal diet (BD)-fed mice resulted in an increase in serum alanine aminotransferase (ALT) levels. Surprisingly, combined administration of very low dose lipopolysaccharide in palmitate-treated mice led to a marked increase in serum ALT levels despite BD-fed conditions. Administration of palmitate alone in BD-fed mice caused inflammatory cell infiltration and liver fibrosis mediated by the toll-like receptor 4 pathway without ALT elevation. In addition, a significant correlation between serum free fatty acid levels and liver fibrosis stage was observed in patients with NAFLD. These results indicate that palmitate may play crucial roles in the pathogenesis of NAFLD in the presence of gut-derived endotoxin.

In this study, we first established the doxorubicin-induced cardiotoxicity (DIC) model with C57BL/6 mice and confirmed cardiac dysfunction with transthoracic echocardiography examination. RNA-sequencing was then performed to explore the potential mechanisms and transcriptional changes in the process. The metabolic pathway, biosynthesis of polyunsaturated fatty acid was significantly altered in DOX-treated murine heart, and Acot1 was one of the leading-edge core genes. We then investigated the role of Acot1 to ferroptosis that was reported recently to be related to DIC. The induction of ferroptosis in the DOX-treated heart was confirmed by transmission electron microscopy, and the inhibition of ferroptosis using Fer-1 effectively prevented the cardiac injury as well as the ultrastructure changes of cardiomyocyte mitochondrial. Both in vitro and in vivo experiments proved the downregulation of Acot1 in DIC, which can be partially prevented with Fer-1 treatment. Overexpression of Acot1 in cell lines showed noteworthy protection to ferroptosis, while the knock-down of Acot1 sensitized cardiomyocytes to ferroptosis by DIC. Finally, the heart tissue of αMHC-Acot1 transgenic mice presented altered free fatty acid composition, indicating that the benefit of Acot1 in the inhibition of ferroptosis lies biochemically and relates to its enzymatic function in lipid metabolism in DIC. The current study highlights the importance of ferroptosis in DIC and points out the potential protective role of Acot1 in the process. The beneficial role of Acot1 may be related to its biochemical function by shaping the lipid composition. In all, Acot1 may become a potential treating target in preventing DIC by anti-ferroptosis.

A highly specific chemical crosslinking method is used to trap a complex between an acyl carrier protein and a fatty acid dehydratase during fatty acid biosynthesis; subsequent X-ray crystallography, NMR spectroscopy and molecular dynamics simulations techniques enable the detailed study of this complex. Acyl carrier protein structures revealed During fatty acid and polyketide biosynthesis the growing polymer chain is stabilized by acyl carrier proteins (ACPs), but the transient nature of the process makes it difficult to visualize the molecular mechanisms involved. Two papers published in this issue of Nature use strategies that circumvent this problem. Ali Masoudi et al . solve the X-ray crystal structures of an ACP from Escherichia coli bound to LpxD, an acyltransferase in the lipid A biosynthetic pathway, in three different states: an intact acyl-ACP, a hydrolysed-acyl-ACP, and a holo-ACP form. Alignment of these structures makes it possible to visualize the conformational changes that take place in the ACP during catalysis. Chi Nguyen et al . use a crosslinking probe to tether an ACP to an active site histidine of one of its catalytic enzymes, the dehydratase FabA from E. coli . They obtain a high-resolution X-ray crystal structure of the stabilized ACP–FabA complex and use NMR spectroscopy to probe the dynamics of ACP–FabA interactions. Their experiments support a 'switchblade' model. This crosslink-probe approach can be applied to other carrier protein partners in metabolic and signalling pathways. Acyl carrier protein (ACP) transports the growing fatty acid chain between enzymatic domains of fatty acid synthase (FAS) during biosynthesis 1 . Because FAS enzymes operate on ACP-bound acyl groups, ACP must stabilize and transport the growing lipid chain 2 . ACPs have a central role in transporting starting materials and intermediates throughout the fatty acid biosynthetic pathway 3 , 4 , 5 . The transient nature of ACP–enzyme interactions impose major obstacles to obtaining high-resolution structural information about fatty acid biosynthesis, and a new strategy is required to study protein–protein interactions effectively. Here we describe the application of a mechanism-based probe that allows active site-selective covalent crosslinking of AcpP to FabA, the Escherichia coli ACP and fatty acid 3-hydroxyacyl-ACP dehydratase, respectively. We report the 1.9 Å crystal structure of the crosslinked AcpP–FabA complex as a homodimer in which AcpP exhibits two different conformations, representing probable snapshots of ACP in action: the 4′-phosphopantetheine group of AcpP first binds an arginine-rich groove of FabA, then an AcpP helical conformational change locks AcpP and FabA in place. Residues at the interface of AcpP and FabA are identified and validated by solution nuclear magnetic resonance techniques, including chemical shift perturbations and residual dipolar coupling measurements. These not only support our interpretation of the crystal structures but also provide an animated view of ACP in action during fatty acid dehydration. These techniques, in combination with molecular dynamics simulations, show for the first time that FabA extrudes the sequestered acyl chain from the ACP binding pocket before dehydration by repositioning helix III. Extensive sequence conservation among carrier proteins suggests that the mechanistic insights gleaned from our studies may be broadly applicable to fatty acid, polyketide and non-ribosomal biosynthesis. Here the foundation is laid for defining the dynamic action of carrier-protein activity in primary and secondary metabolism, providing insight into pathways that can have major roles in the treatment of cancer, obesity and infectious disease.

Metabolomics analysis of stem cells and differentiated cells points to chemical unsaturation as a key feature of stem cell metabolites. Manipulation of these metabolites' concentrations directly influences stem cell behavior, highlighting biological oxidation as a driver for differentiation. Metabolites offer an important unexplored complementary approach to understanding the pluripotency of stem cells. Using MS-based metabolomics, we show that embryonic stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. By monitoring the reduced and oxidized glutathione ratio as well as ascorbic acid levels, we demonstrate that the stem cell redox status is regulated during differentiation. On the basis of the oxidative biochemistry of the unsaturated metabolites, we experimentally manipulated specific pathways in embryonic stem cells while monitoring the effects on differentiation. Inhibition of the eicosanoid signaling pathway promoted pluripotency and maintained levels of unsaturated fatty acids. In contrast, downstream oxidized metabolites (for example, neuroprotectin D1) and substrates of pro-oxidative reactions (for example, acyl-carnitines), promoted neuronal and cardiac differentiation. We postulate that the highly unsaturated metabolome sustained by stem cells allows them to differentiate in response to in vivo oxidative processes such as inflammation.