Abstract
The endoplasmic reticulum (ER) plays a crucial role in protein folding, assembly, and secretion. Disruption of ER homeostasis may lead to accumulation of misfolded or unfolded proteins in the ER lumen, a condition referred to as ER stress. In response to ER stress, a signal transduction pathway known as the unfolded protein response (UPR) is activated. UPR activation allows the cell to cope with an increased protein-folding demand on the ER. Recent studies have shown that ER stress/UPR activation plays a critical role in lipid metabolism and homeostasis. ER-stress-dependent dysregulation of lipid metabolism may lead to dyslipidemia, insulin resistance, cardiovascular disease, type 2 diabetes, and obesity. In this paper, we examine recent findings illustrating the important role ER stress/UPR signalling pathways play in regulation of lipid metabolism, and how they may lead to dysregulation of lipid homeostasis.
Highlights
The liver plays a central role in whole body lipid homeostasis
Ligand-activated nuclear peroxisome-proliferator-activated receptor-γ (PPARγ) heterodimerizes with retinoid X receptors (RXRs) resulting in expression of its target genes such as CD36, a fatty acid transport protein involved in the transport and metabolism of intracellular FA [40]
The unfolded protein response (UPR) in mammalian cells is composed of three signalling branches which are initiated by three endoplasmic reticulum (ER) transmembrane sensors, inositol-requiring protein 1 (IRE1), double-stranded RNA-dependent protein kinase-like ER kinase (PERK), and activating transcription factor 6 (ATF6)
Summary
The liver plays a central role in whole body lipid homeostasis Metabolic signals such as carbohydrates and dietary fatty acids regulate hepatic gene expression leading to glycolytic and lipogenic signalling pathways. Under fasting conditions when insulin levels are low and glucagon levels are high, FA oxidation or lipolysis occurs which allows for mobilization of FA and uptake by the liver [3] Disruption in these homeostatic mechanisms may lead to the development of dyslipidemia, insulin resistance, fatty liver, and excess adipose mass, causing cardiovascular disease and diabetes. In recent years, increasing evidence suggests that ER stress and UPR activation can regulate cellular processes beyond ER protein folding and can play crucial roles in lipid metabolism [4,5,6,7,8,9,10]. Potential therapeutic approaches targeting the ER stress response in obesity and dyslipidemia will be discussed
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