Highly sophisticated mechanisms that modulate protein structure and function, which involve synthesis and degradation, have evolved to maintain cellular homeostasis. Perturbations in these mechanisms can lead to protein dysfunction as well as deleterious cell processes. Therefore in recent years the etiology of a great number of diseases has been attributed to failures in mechanisms that modulate protein structure. Interconnections among metabolic and cell signaling pathways are critical for homeostasis to converge on mechanisms associated with protein folding as well as for the preservation of the native structure of proteins. For instance, imbalances in secretory protein synthesis pathways lead to a condition known as endoplasmic reticulum (ER) stress which elicits the adaptive unfolded protein response (UPR). Therefore, taking this into consideration, a key part of this paper is developed around the protein folding phenomenon, and cellular mechanisms which support this pivotal condition. We provide an overview of chaperone protein function, UPR via, spatial compartmentalization of protein folding, proteasome role, autophagy, as well as the intertwining between these processes. Several diseases are known to have a molecular etiology in the malfunction of mechanisms responsible for protein folding and in the shielding of native structure, phenomena which ultimately lead to misfolded protein accumulation. This review centers on our current knowledge about pathways that modulate protein folding, and cell responses involved in protein homeostasis.

Fatty acids are involved in several metabolic processes, including the development of metabolic and cardiovascular diseases. In recent years a disease that has received escalated interest is type 2 diabetes (T2D). Many contributing factors including a high-caloric diet rich in dietary saturated fats have been broadly characterized as triggers of T2D. Insulin resistance resulting from a high saturated fat diet leads to alterations in lipid cellular intake and accumulation which generate lipotoxic conditions, a key phenomenon in the metabolism of β-cells. Alternatively, unsaturated fatty acids have been described to show opposite effects in pancreatic β-cells. The purpose of this work is to perform a critical analysis of the complex role of saturated and unsaturated fatty acids in β-cell metabolism. We discuss the diverse effects main dietary fatty acids have upon pancreatic β-cell metabolism as a key factor to maintain homeostasis by focusing in the cellular and molecular mechanisms involved in the development and progression of T2D. For instance, modifications in protein homeostasis as well as the intracellular management of lipid metabolism which are associated with inflammatory pathways. These conditions initiate critical metabolic rearrangements, that in turn have repercussions on insulin β-cell metabolism. This review allows an integral and broad understanding of different functions of fatty acids inside β-cells, being important metabolites for novel therapeutic targets in T2D treatment.

Metabolic overload by saturated fatty acids (SFA), which comprises β-cell function, and impaired glucose-stimulated insulin secretion are frequently observed in patients suffering from obesity and type 2 diabetes mellitus. The increase of intracellular Ca²⁺ triggers insulin granule release, therefore several mechanisms regulate Ca²⁺ efflux within the β-cells, among others, the plasma membrane Ca²⁺-ATPase (PMCA). In this work, we describe that lipotoxicity mediated mainly by the saturated palmitic acid (PA) (16C) is associated with loss of protein homeostasis (proteostasis) and potentially cell viability, a phenomenon that was induced to a lesser extent by stearic (18C), myristic (14C) and lauric (12C) acids. PA was localized on endoplasmic reticulum, activating arms of the unfolded protein response (UPR), as also promoted by lipopolysaccharides (LPS)-endotoxins. In particular, our findings demonstrate an alteration in PMCA1/4 expression caused by PA and LPS which trigger the UPR, affecting not only insulin release and contributing to β-cell mass reduction, but also increasing reactive nitrogen species. Nonetheless, stearic acid (SA) did not show these effects. Remarkably, the proteolytic degradation of PMCA1/4 prompted by PA and LPS was avoided by the action of monounsaturated fatty acids such as oleic and palmitoleic acid. Oleic acid recovered cell viability after treatment with PA/LPS and, more interestingly, relieved endoplasmic reticulum (ER) stress. While palmitoleic acid improved the insulin release, this fatty acid seems to have more relevant effects upon the expression of regulatory pumps of intracellular Ca²⁺. Therefore, chain length and unsaturation of fatty acids are determinant cues in proteostasis of β-cells and, consequently, on the regulation of calcium and insulin secretion.

Atherosclerosis together with multiple sclerosis, psoriasis and rheumatoid arthritis can be used as examples of chronic inflammatory diseases associated with multifactorial components that evolve over the years. Nevertheless, an important difference between these diseases relies on the fact that atherosclerosis develops from early ages where inflammation dominates the very beginning of the disease. This review highlights the inflammatory nature of atherosclerosis and the role the immune system plays in the process of atherogenesis. Although treatment of atherosclerosis has been for years based on lipid-lowering therapies reducing a series of risk factors, the degree of success has been only limited because cardiovascular complications related to the evolution of atherosclerotic lesions continue to appear in the population worldwide. In this sense, alternative treatments for atherosclerosis have come into play where both innate and adaptive immunity have been proposed to modulate atherosclerosis-associated inflammatory phenomena. When tested for their atheroprotective properties, several immunogens have been studied through passive and active immunization with good results and, therefore, the strategy through vaccination to control the disease has been made possible. Many experimental pre-clinical studies demonstrating proof of concept that vaccination using DNA and protein with an effective use of adjuvants and the optimal route of administration now provide a tangible new therapeutic approach that sets the stage for several of these vaccines to be tested in large, randomized, long-term clinical studies. A vaccine ready for human use will only be accomplished through the close association between academia, regulatory government organizations and private industry, allowing the reality of a simple and successful therapy to reduce atherosclerosis and its severe clinical complications.

Ceramides are key lipids in energetic-metabolic pathways and signaling cascades, modulating critical physiological functions in cells. While synthesis of ceramides is performed in endoplasmic reticulum (ER), which is altered under overnutrition conditions, proteins associated with ceramide metabolism are located on membrane arrangement of mitochondria and ER (MAMs). However, ceramide accumulation in meta-inflammation, condition that associates obesity with a chronic low-grade inflammatory state, favors the deregulation of pathways such as insulin signaling, and induces structural rearrangements on mitochondrial membrane, modifying its permeability and altering the flux of ions and other molecules. Considering the wide biological processes in which sphingolipids are implicated, they have been associated with diseases that present abnormalities in their energetic metabolism, such as breast cancer. In this sense, sphingolipids could modulate various cell features, such as growth, proliferation, survival, senescence, and apoptosis in cancer progression; moreover, ceramide metabolism is associated to chemotherapy resistance, and regulation of metastasis. Cell–cell communication mediated by exosomes and lipoproteins has become relevant in the transport of several sphingolipids. Therefore, in this work we performed a comprehensive analysis of the state of the art about the multifaceted roles of ceramides, specifically the deregulation of ceramide metabolism pathways, being a key factor that could modulate neoplastic processes development. Under specific conditions, sphingolipids perform important functions in several cellular processes, and depending on the preponderant species and cellular and/or tissue status can inhibit or promote the development of metabolic and potentially breast cancer disease.