ER Dysfunction under Metabolic Stress

Regulation of ER Calcium Homeostasis

While the ER is equipped with powerful adaptive programs to preserve its integrity, it succumbs to metabolic stress, such as the case in obesity.  To explore the molecular mechanisms behind this maladaptive state of ER facing metabolic stress, we have systematically explored all ER resident proteins, membrane lipids, as well as ER-associated ribosomes, and translational profiles in highly purified ER fractions in liver tissue and compared the compositional alterations in lean and obese state.  These efforts illustrated that calcium regulation is aberrant in the ER, and highlighted the impact of lipogenesis and changes in the ER membrane composition of phospholipids in impairing SERCA function in the liver during obesity. We explore how disruption of calcium homeostasis can lead to hallmarks of obesity and diabetes: increased ER stress, increased glucose production, abrogated insulin sensitivity, and abnormal lipid metabolism with a focus on ER and mitochondria calcium regulatory proteins during metabolic fluctuations and challenges.  We hope to learn more about the metabolic effects of these versatile signaling molecules and examine potential alterations in other tissues, such as adipose tissue, that are important for our body’s metabolic mission. We hope to utilize this knowledge to create potential novel therapeutics that involves proper regulation of calcium in metabolic diseases. ​

Regulation of Calcium Homeostasis

Inflammation and ER Dysfunction

During our studies exploring the mechanisms underlying the emergence of obesity-associated chronic inflammatory and stress responses such as JNK activation, we discovered abnormal ER adaptive responses and the unfolded protein response (UPR) activity profiles in both experimental and human obesity. These studies suggested that ER stress and dysfunction may be proximal to the emergence of metaflammation. In fact, most recently, we discovered that in adipose tissue, abnormal ER calcium homeostasis is a critical trigger for inflammation- and obesity-related JNK activation and impaired insulin action in adipose tissue, and abnormal systemic glucose metabolism. These discoveries support a model that ER dysfunction and stress is a critical instigators of metaflammation.  Interestingly, however, in several different disease contexts, such as Type 1 and type 2 diabetes, we also recognized that an inflammatory environment can also impair the canonical defense systems of the ER in the liver tissue and endocrine pancreas. For example, the inflammation-induced nitrosative stress, leads to posttranslational modification of key UPR signaling molecules such as IRE1, and blocks its adaptive capacity. Hence, inflammation can also be proximal to ER stress and generate a vicious cycle of ER dysfunction, which also sustains metaflammation. We actively investigate the mechanisms involved in the integration of immunometabolic responses and their abnormal regulation in metabolic diseases with the goal of producing new therapeutic strategies and tools.

Suggested Readings:

Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, Lin X, Watkins SM, Ivanov AR, Hotamisligil GS. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature. 2011 May 26;473(7348):528-31. doi: 10.1038/nature09968. Abstract | PDF

Arruda AP, Pers BM, Parlakgul G, Güney E, Goh T, Cagampan E, Lee GY, Goncalves RL, Hotamisligil GS. Defective STIM-mediated store operated Ca2+ entry in hepatocytes leads to metabolic dysfunction in obesity. Elife. 2017 Dec 15;6:e29968. doi: 10.7554/eLife.29968. Full Text

Guney E, Arruda AP, Parlakgul G, Cagampan E, Min N, Lee GY, Greene L, Tsaousidou E, Inouye K, Han MS, Davis RJ, Hotamisligil GS. Aberrant Ca2+ signaling by IP3Rs in adipocytes links inflammation to metabolic dysregulation in obesity. Sci Signal. 2021 Dec 14;14(713):eabf2059. doi: 10.1126/scisignal.abf2059. Epub 2021 Dec 14. Abstract

Yang L, Calay ES, Fan J, Arduini A, Kunz RC, Gygi SP, Yalcin A, Fu S, Hotamisligil GS. METABOLISM. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science. 2015 Jul 31;349(6247):500-6. doi: 10.1126/science.aaa0079. Abstract

Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006 Aug 25;313(5790):1137-40. doi: 10.1126/science.1128294. Abstract

Fu S, Yalcin A, Lee GY, Li P, Fan J, Arruda AP, Pers BM, Yilmaz M, Eguchi K, Hotamisligil GS. Phenotypic assays identify azoramide as a small-molecule modulator of the unfolded protein response with antidiabetic activity. Sci Transl Med. 2015 Jun 17;7(292):292ra98. doi: 10.1126/scitranslmed.aaa9134. Abstract