Diet, hormones, gene transcription, and posttranslational modifications control the hepatic metabolism of FAs; metabolic dysregulation causes chronic diseases, including cardiovascular disease, and ...warrants exploration into the mechanisms directing FA and triacylglycerol (TAG) synthesis and degradation. Long-chain FA metabolism begins by formation of an acyl-CoA by a member of the acyl-CoA synthetase (ACSL) family. Subsequently, TAG synthesis begins with acyl-CoA esterification to glycerol-3-phosphate by a member of the glycerol-3-phosphate acyltransferase (GPAT) family. Our studies of the isoforms ACSL1 and GPAT1 strongly suggest that these proteins are members of larger protein assemblies (interactomes). ACSL1 targeted to the ER interacts with peroxisomal, lipid droplet, and tethering proteins, uncovering a dynamic role for ACSL1 in organelle and lipid droplet interactions. On the outer mitochondrial membrane (OMM), PPARα upregulates ACSL1, which interacts with proteins believed to tether lipid droplets to the OMM. In contrast, GPAT1 is upregulated nutritionally by carbohydrate and insulin in a coordinated sequence of enzyme reactions, from saturated FA formation via de novo lipogenesis to FA esterification by GPAT1 and entry into the TAG biosynthesis pathway. We propose that involved enzymes form a dynamic protein interactome that facilitates esterification and that other lipid-metabolizing pathways will exist in similar physiologically regulated interactomes. Display omitted
Facing fraud in my lab Coleman, Rosalind A
Science (American Association for the Advancement of Science),
12/2023, Letnik:
382, Številka:
6677
Journal Article
Mammalian lipid droplets (LDs), first described as early as the 1880s, were virtually ignored for more than 100 years. Between 1991 and the early 2000s, however, a series of discoveries and ...conceptual breakthroughs led to a resurgent interest in obesity as a disease, in the metabolism of intracellular triacylglycerol (TAG), and in the physical locations of LDs as cellular structures with their associated proteins. Insights included the recognition that obesity underlies major chronic diseases, that appetite is hormonally controlled, that hepatic steatosis is not a benign finding, and that diabetes might fundamentally be a disorder of lipid metabolism. In this brief review, I describe the metamorphosis of LDs from overlooked globs of stored fat to dynamic organelles that control insulin resistance, mitochondrial oxidation, and viral replication.
•Lipid droplets (LDs) have been noted in plant and animal cells since the 1880s.•Interest in LDs grew because of discoveries and conceptual changes in the 1990s.•LDs were ignored as organelles until specific associated proteins and functions were identified.•LDs are intrinsically associated with normal cellular and organismal energy metabolism.•LDs are functional linked to chronic diseases such as diabetes, cardiovascular disease, and cancer.
The heart's extraordinary metabolic flexibility allows it to adapt to normal changes in physiology in order to preserve its function. Alterations in the metabolic profile of the heart have also been ...attributed to pathological conditions such as ischemia and hypertrophy; however, research during the past decade has established that cardiac metabolic adaptations can precede the onset of pathologies. It is therefore critical to understand how changes in cardiac substrate availability and use trigger events that ultimately result in heart dysfunction. This review examines the mechanisms by which the heart obtains fuels from the circulation or from mobilization of intracellular stores. We next describe experimental models that exhibit either an increase in glucose use or a decrease in FA oxidation, and how these aberrant conditions affect cardiac metabolism and function. Finally, we highlight the importance of alternative, relatively under-investigated strategies for the treatment of heart failure. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
•The heart adapts to normal changes in physiology by switching metabolic substrates.•Altered cardiac metabolism has also been identified under pathological conditions.•Increased glucose use may precede the onset of various pathologies.•Decreased fatty acid oxidation does not ameliorate dysfunction in multiple models.•Alternative strategies investigating transendothelial fuel transport are warranted.
Acyl-CoA metabolism and partitioning Grevengoed, Trisha J; Klett, Eric L; Coleman, Rosalind A
Annual review of nutrition,
01/2014, Letnik:
34
Journal Article
Recenzirano
Odprti dostop
Long-chain fatty acyl-coenzyme As (CoAs) are critical regulatory molecules and metabolic intermediates. The initial step in their synthesis is the activation of fatty acids by one of 13 long-chain ...acyl-CoA synthetase isoforms. These isoforms are regulated independently and have different tissue expression patterns and subcellular locations. Their acyl-CoA products regulate metabolic enzymes and signaling pathways, become oxidized to provide cellular energy, and are incorporated into acylated proteins and complex lipids such as triacylglycerol, phospholipids, and cholesterol esters. Their differing metabolic fates are determined by a network of proteins that channel the acyl-CoAs toward or away from specific metabolic pathways and serve as the basis for partitioning. This review evaluates the evidence for acyl-CoA partitioning by reviewing experimental data on proteins that are believed to contribute to acyl-CoA channeling, the metabolic consequences of loss of these proteins, and the potential role of maladaptive acyl-CoA partitioning in the pathogenesis of metabolic disease and carcinogenesis.
Lipid droplets (LDs) store metabolic energy and membrane lipid precursors. With excess metabolic energy, cells synthesize triacylglycerol (TG) and form LDs that grow dramatically. It is unclear how ...TG synthesis relates to LD formation and growth. Here, we identify two LD subpopulations: smaller LDs of relatively constant size, and LDs that grow larger. The latter population contains isoenzymes for each step of TG synthesis. Glycerol-3-phosphate acyltransferase 4 (GPAT4), which catalyzes the first and rate-limiting step, relocalizes from the endoplasmic reticulum (ER) to a subset of forming LDs, where it becomes stably associated. ER-to-LD targeting of GPAT4 and other LD-localized TG synthesis isozymes is required for LD growth. Key features of GPAT4 ER-to-LD targeting and function in LD growth are conserved between Drosophila and mammalian cells. Our results explain how TG synthesis is coupled with LD growth and identify two distinct LD subpopulations based on their capacity for localized TG synthesis.
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► Triacylglyceride (TG) synthesis is coupled with lipid droplet (LD) growth ► Two LD populations exist: growing LDs, containing TG enzymes, and small LDs ► Specific TG synthesis enzymes move from the ER to LDs through membrane bridges ► LD localization of TG enzymes mediates expansion of a subset of LDs
Lipid droplets (LDs) store metabolic energy and membrane lipid precursors. Wilfling et al. identify two LD populations distinct in their capacity for localized triacylglycerol (TG) synthesis, which is coupled to LD growth. TG synthesis enzymes relocate via membrane bridges from the ER to the LD surface to mediate LD expansion.
Because the signaling eicosanoids, epoxyeicosatrienoic acids (EETs) and HETEs, are esterified to membrane phospholipids, we asked which long-chain acyl-CoA synthetase (ACSL) isoforms would activate ...these molecules and whether the apparent FA substrate preferences of each ACSL isoform might differ depending on whether it was assayed in mammalian cell membranes or as a purified bacterial recombinant protein. We found that all five ACSL isoforms were able to use EETs and HETEs as substrates and showed by LC-MS/MS that ACSLs produce EET-CoAs. We found differences in substrate preference between ACS assays performed in COS7 cell membranes and recombinant purified proteins. Similarly, preferences and Michaelis-Menten kinetics for long-chain FAs were distinctive. Substrate preferences identified for the purified ACSLs did not correspond to those observed in ACSL-deficient mouse models. Taken together, these data support the concept that each ACSL isoform exhibits a distinct substrate preference, but apparent substrate specificities depend upon multiple factors including membrane character, coactivators, inhibitors, protein interactions, and posttranslational modification.
Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) is caused by loss-of-function mutations in SEIPIN, a protein implicated in both adipogenesis and lipid droplet expansion but whose molecular ...function remains obscure. Here, we identify physical and functional interactions between SEIPIN and microsomal isoforms of glycerol-3-phosphate acyltransferase (GPAT) in multiple organisms. Compared to controls, GPAT activity was elevated in SEIPIN-deficient cells and tissues and GPAT kinetic values were altered. Increased GPAT activity appears to underpin the block in adipogenesis and abnormal lipid droplet morphology associated with SEIPIN loss. Overexpression of Gpat3 blocked adipogenesis, and Gpat3 knockdown in SEIPIN-deficient preadipocytes partially restored differentiation. GPAT overexpression in yeast, preadipocytes, and fly salivary glands also formed supersized lipid droplets. Finally, pharmacological inhibition of GPAT in Seipin−/− mouse preadipocytes partially restored adipogenesis. These data identify SEIPIN as an evolutionarily conserved regulator of microsomal GPAT and suggest that GPAT inhibitors might be useful for the treatment of human BSCL2 patients.
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•Loss of SEIPIN function causes Berardinelli-Seip congenital lipodystrophy 2•Lack of SEIPIN increases glycerol-3-phosphate acyltransferase (GPAT) activity•Inhibiting GPAT enhances differentiation of SEIPIN-deficient preadipocytes•Inhibiting GPAT corrects abnormal lipid droplet morphology in SEIPIN deficiency
Pagac et al. find that SEIPIN, which has been linked to Berardinelli-Seip congenital lipodystrophy 2, interacts with microsomal glycerol-3-phosphate acyltransferase (GPAT) and influences its activity. Increased GPAT activity appears to underlie the block in adipogenesis and abnormal lipid droplet morphology associated with SEIPIN loss.
Lipid droplets (LDs) are intracellular organelles that store neutral lipids within cells. Over the last two decades there has been a dramatic growth in our understanding of LD biology and, in ...parallel, our understanding of the role of LDs in health and disease. In its simplest form, the LD regulates the storage and hydrolysis of neutral lipids, including triacylglycerol and/or cholesterol esters. It is becoming increasingly evident that alterations in the regulation of LD physiology and metabolism influence the risk of developing metabolic diseases such as diabetes. In this review we provide an update on the role of LD-associated proteins and LDs in metabolic disease.
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