Lipotoxicity: when tissues overeat

Schaffer, Jean E.

doi:10.1097/00041433-200306000-00008

Cited by 797 publications

(666 citation statements)

References 67 publications

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“…11,28 Certain FFAs are potentially cytotoxic, and in vitro studies in different cell lines including hepatocytes have implicated increased cellular FFA levels as a trigger of apoptotic cell death. 12,29,30 Our current data demonstrates that incubation of human and murine hepatocytes with FFAs results in dose-and saturationdependent mitochondrial dysfunction. The saturated FFA palmitate at concentrations that mimic the levels of this FFA in the circulation of humans with metabolic syndrome 31 induces significant mitochondrial membrane permeabilization and increased ROS production.…”

Section: Discussionmentioning

confidence: 58%

The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity

et al. 2008

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Section: Discussionmentioning

confidence: 58%

The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity

et al. 2008

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“…The observation that cardiac myocyte lipid overload causes cardiomyopathy in genetic mouse models, without systemic abnormalities of insulin or glucose metabolism, supports the notion that excess lipids can be cardiotoxic (4,5,7,32). Membrane lipid remodeling, endoplasmic reticulum and oxidative stress, and production of toxic lipid species, such as ceramides, have been implicated as potential mechanisms of cardiac lipotoxicity (12,23).…”

mentioning

confidence: 54%

“…A key feature of the diabetic heart is the accumulation of myocardial lipid, which is thought to contribute to myocyte dysfunction and cell loss (15,20,23,25). However, the mechanisms involved in cardiac lipotoxicity in this disease are unresolved.…”

Section: Discussionmentioning

confidence: 99%

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Schilling

Machkovech

Kim

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Schilling JD, Machkovech HM, Kim AH, Schwedwener R, Schaffer JE. Macrophages modulate cardiac function in lipotoxic cardiomyopathy. Am J Physiol Heart Circ Physiol 303: H1366 -H1373, 2012. First published October 5, 2012; doi:10.1152/ajpheart.00111.2012.-Diabetes is associated with myocardial lipid accumulation and an increased risk of heart failure. Although cardiac myocyte lipid overload is thought to contribute to the pathogenesis of cardiomyopathy in the setting of diabetes, the mechanism(s) through which this occurs is not well understood. Increasingly, inflammation has been recognized as a key pathogenic feature of lipid excess and diabetes. In this study, we sought to investigate the role of inflammatory activation in the pathogenesis of lipotoxic cardiomyopathy using the ␣-myosin heavy chain promoter-driven long-chain acylCoA synthetase 1 (MHC-ACS) transgenic mouse model. We found that several inflammatory cytokines were upregulated in the myocardium of MHC-ACS mice before the onset of cardiac dysfunction, and this was accompanied by macrophage infiltration. Depletion of macrophages with liposomal clodrolip reduced the cardiac inflammatory response and improved cardiac function. Thus, in this model of lipotoxic cardiac injury, early induction of inflammation and macrophage recruitment contribute to adverse cardiac remodeling. These findings have implications for our understanding of heart failure in the setting of obesity and diabetes. heart failure; diabetes; inflammation OBESITY AND DIABETES ARE SIGNIFICANT risk factors for the development of heart failure (11). In many diabetic patients, this can occur in the absence of underlying coronary artery disease or hypertension, a phenomenon known as diabetic cardiomyopathy (1). The pathogenesis of diabetic cardiomyopathy is complex; however, myocardial lipid overload is a pathologic feature of this condition in humans and in animal models (6,7,12,25). The observation that cardiac myocyte lipid overload causes cardiomyopathy in genetic mouse models, without systemic abnormalities of insulin or glucose metabolism, supports the notion that excess lipids can be cardiotoxic (4,5,7,32). Membrane lipid remodeling, endoplasmic reticulum and oxidative stress, and production of toxic lipid species, such as ceramides, have been implicated as potential mechanisms of cardiac lipotoxicity (12,23).Systemic inflammation is another hallmark of obesity and diabetes and has been shown to correlate with the risk of heart failure in patients with these metabolic conditions (2). This raises the intriguing possibility that lipid-induced inflammatory responses might contribute to cardiac dysfunction in obesity and diabetes. Much of what is known regarding the link between diabetes and inflammation has come from investigations of adipose tissue. In humans and animals, obesity triggers the recruitment of macrophages to white adipose tissue, which is followed by release of inflammatory mediators and the onset of insulin resistance (26,29). When this response is interrupted in mice fed...

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“…Our finding that IRE1 maintains the expression of several important proatherogenic genes in macrophages suggests that, when induced by metabolic stress, heightened IRE1 activity could drive the atherosclerotic process. One important activating signal for the UPR in macrophages is exposure to excessive amounts of lipids, which elicits toxicity (14,28,41). This lipotoxicity results in increased production of reactive oxygen species (ROS), ER stress, and inflammation, and it can result in apoptosis (41).…”

Section: Resultsmentioning

confidence: 99%

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Tufanlı

Telkoparan-Akillilar

Acosta‐Alvear

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

167

195

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Metaflammation, an atypical, metabolically induced, chronic lowgrade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ERresident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogenic genes, including several important cytokines and chemokines. We show that IRE1 inhibitors uncouple lipid-induced ER stress from inflammasome activation in both mouse and human macrophages. In vivo, these IRE1 inhibitors led to a significant decrease in hyperlipidemia-induced IL-1β and IL-18 production, lowered T-helper type-1 immune responses, and reduced atherosclerotic plaque size without altering the plasma lipid profiles in apolipoprotein E-deficient mice. These results show that pharmacologic modulation of IRE1 counteracts metaflammation and alleviates atherosclerosis.endoplasmic reticulum stress | unfolded protein response | metaflammation | lipotoxicity | atherosclerosis C omplex molecular interactions between environment, diet, and genetics that take place at the metabolic and immune interface provoke a low-grade, chronic inflammatory responsemetaflammation-that engages cells of the immune system (macrophages, neutrophils, and lymphocytes) and metabolic tissues (adipocytes, hepatocytes, and pancreatic cells) (1). An important primer for metaflammation is chronic metabolic overloading of organelles, such as the endoplasmic reticulum (ER) and mitochondria, which results in impairment of their functions (2).The ER serves essential cellular functions that include the synthesis and folding of secreted and transmembrane proteins, calcium storage, and lipid synthesis for membrane biogenesis or energy storage. Disruption of any of these functions leads to ER stress and the subsequent activation of an elaborate network of adaptive responses, collectively known as the unfolded protein response (UPR) (3). The UPR reestablishes homeostasis through both transcriptional and translational layers of control. The UPR signals through three mechanistically distinct branches that are initiated by the ER-resident protein folding sensors inositolrequiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) (3).IRE1 controls the phylogenetically most conserved branch of the UPR found from fungi to metazoans. It has an ER-lumenal sensor domain that recognizes unfolded peptides and cytosolic kinase and endoribonuclease (RNase) domains that relay the information to downstrea...

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Lipotoxicity: when tissues overeat

Cited by 797 publications

References 67 publications

The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity

The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

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