A guide to understanding endoplasmic reticulum stress in metabolic disorders

Abstract

Background: The global rise of metabolic disorders, such as obesity, type 2 diabetes, and cardiovascular disease, demands a thorough molecular understanding of the cellular mechanisms that govern health or disease. The endoplasmic reticulum (ER) is a key organelle for cellular function and metabolic adaptation and, therefore disturbed ER function, known as "ER stress," is a key feature of metabolic disorders.

Scope of review: As ER stress remains a poorly defined phenomenon, this review provides a general guide to understanding the nature, etiology, and consequences of ER stress in metabolic disorders. We define ER stress by its type of stressor, which is driven by proteotoxicity, lipotoxicity, and/or glucotoxicity. We discuss the implications of ER stress in metabolic disorders by reviewing evidence implicating ER phenotypes and organelle communication, protein quality control, calcium homeostasis, lipid and carbohydrate metabolism, and inflammation as key mechanisms in the development of ER stress and metabolic dysfunction.

Major conclusions: In mammalian biology, ER is a phenotypically and functionally diverse platform for nutrient sensing, which is critical for cell type-specific metabolic control by hepatocytes, adipocytes, muscle cells, and neurons. In these cells, ER stress is a distinct, transient state of functional imbalance, which is usually resolved by the activation of adaptive programs such as the unfolded protein response (UPR), ER-associated protein degradation (ERAD), or autophagy. However, challenges to proteostasis also impact lipid and glucose metabolism and vice versa. In the ER, sensing and adaptive measures are integrated and failure of the ER to adapt leads to aberrant metabolism, organelle dysfunction, insulin resistance, and inflammation. In conclusion, the ER is intricately linked to a wide spectrum of cellular functions and is a critical component in maintaining and restoring metabolic health.

Keywords: Autophagy; Endoplasmic reticulum; Inflammation; Obesity; UPR.

Graphical abstract

Figure 1

Cellular protein quality control. Three major cellular programs are responsible for proteostasis. The UPR is activated by binding of unfolded proteins to chaperone proteins and the luminal parts of the UPR sensors. The ATF6, PERK, and IRE1α pathways attenuate proteostatic burden by promoting the transcription of folding chaperones and inhibiting protein translation via EIF2α. In ERAD, misfolded substrates are shuttled from the ER lumen into the cytosol, where they undergo ubiquitination degradation by the proteasome. During proteostatic stress, the transcription factor Nfe2l1 escapes proteasomal degradation and promotes transcription of proteasome subunits. In autophagy regulated by mTORC1, redundant proteins and organelles are degraded in autolysosomes.

Figure 2

Calcium homeostasis in the ER. The high calcium-ion gradient across the ER membrane between lumen and the cytosol is maintained through several mechanisms. SOCE allows calcium transfer from the extracellular environment to the ER. SERCA continuously “pumps” calcium into the ER lumen. RyR reduces high levels of ER-calcium. ITPR shuttles calcium to the mitochondria through MAM. Obesity leads to ER-calcium depletion, which disrupts ER homeostasis and hinders proper folding of proteins. These disturbances promote ER stress and cellular dysfunction.

Figure 3

ER lipid metabolism in obesity. As a result of high-fat diet consumption, cells are exposed to high levels of (saturated) fatty acids and cholesterol. High levels of membrane fatty acids and cholesterol change the membrane composition and lead to ER stress. Cells have several mechanisms to attenuate lipotoxicity: DGAT1 re-esterifies fatty acids and ACAT esterifies cholesterol for safe storage in lipid droplets as triglycerides or cholesterol esters, respectively. While the SREBP/SCAP system responds to low levels of ER cholesterol, high levels of ER cholesterol block NFE2L1 proteolytic cleavage and lead to fewer proteasome genes and de-repression of inflammation genes.

Figure 4

Immunometabolic interplay in obesity. In obesity, immune cells and parenchymal cells are in crosstalk as they infiltrate metabolic tissues. Excess fatty acids and glucose are sensed by TLRs on macrophages and trigger an IREα response, which releases pro-inflammatory cytokines. Metabolic disorders are also characterized by the formation of foam cells, which carry a surplus of cholesterol esters and other lipids. Cytokines produced by the immune cells are sensed by parenchymal cells and trigger the activation of stress kinases such as JNK, which are directly linked to insulin resistance. IREα in parenchymal cells is also activated by cytokines and leads to transcription of pro-inflammatory mediators. The cGAS-cGAMP-STING pathway is triggered by HFD and enhances inflammatory responses via NF-κB.