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Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment

2016; Elsevier BV; Volume: 57; Issue: 12 Linguagem: Inglês

10.1194/jlr.r066514

1539-7262

Meric Erikci Ertunc, Gökhan S. Hotamışlıgil,

Adipose Tissue and Metabolism

Lipids encompass a wide variety of molecules such as fatty acids, sterols, phospholipids, and triglycerides. These molecules represent a highly efficient energy resource and can act as structural elements of membranes or as signaling molecules that regulate metabolic homeostasis through many mechanisms. Cells possess an integrated set of response systems to adapt to stresses such as those imposed by nutrient fluctuations during feeding-fasting cycles. While lipids are pivotal for these homeostatic processes, they can also contribute to detrimental metabolic outcomes. When metabolic stress becomes chronic and adaptive mechanisms are overwhelmed, as occurs during prolonged nutrient excess or obesity, lipid influx can exceed the adipose tissue storage capacity and result in accumulation of harmful lipid species at ectopic sites such as liver and muscle. As lipid metabolism and immune responses are highly integrated, accumulation of harmful lipids or generation of signaling intermediates can interfere with immune regulation in multiple tissues, causing a vicious cycle of immune-metabolic dysregulation. In this review, we summarize the role of lipotoxicity in metaflammation at the molecular and tissue level, describe the significance of anti-inflammatory lipids in metabolic homeostasis, and discuss the potential of therapeutic approaches targeting pathways at the intersection of lipid metabolism and immune function. Lipids encompass a wide variety of molecules such as fatty acids, sterols, phospholipids, and triglycerides. These molecules represent a highly efficient energy resource and can act as structural elements of membranes or as signaling molecules that regulate metabolic homeostasis through many mechanisms. Cells possess an integrated set of response systems to adapt to stresses such as those imposed by nutrient fluctuations during feeding-fasting cycles. While lipids are pivotal for these homeostatic processes, they can also contribute to detrimental metabolic outcomes. When metabolic stress becomes chronic and adaptive mechanisms are overwhelmed, as occurs during prolonged nutrient excess or obesity, lipid influx can exceed the adipose tissue storage capacity and result in accumulation of harmful lipid species at ectopic sites such as liver and muscle. As lipid metabolism and immune responses are highly integrated, accumulation of harmful lipids or generation of signaling intermediates can interfere with immune regulation in multiple tissues, causing a vicious cycle of immune-metabolic dysregulation. In this review, we summarize the role of lipotoxicity in metaflammation at the molecular and tissue level, describe the significance of anti-inflammatory lipids in metabolic homeostasis, and discuss the potential of therapeutic approaches targeting pathways at the intersection of lipid metabolism and immune function. The term "lipid" is used to identify a large set of hydrophobic and amphiphilic molecules such as free fatty acids, sterols, fatty acid esters, and phospholipids. These molecules are involved in forming fundamental structures in cells and tissues, providing energy for the metabolic needs of organisms, and regulating several homeostatic processes within and outside of cells, including organelle homeostasis, immune function, inter-organ communication, energy metabolism, and cell survival. However, when the balance in their metabolism and composition is altered by environmental or metabolic stress, lifestyle, and genetic or epigenetic factors, lipids can also become critical components of pathophysiological cascades that are detrimental to healthy cell and tissue function. Hence, although lipids play fundamental physiological roles, in excess or in improper composition, they can be highly damaging, leading to organelle dysfunction, cell death, chronic inflammation, and disturbances in energy and substrate metabolism and survival responses. In this review, we primarily focus on the roles of lipid classes that regulate immune responses and signaling mechanisms, which perpetuate a vicious cycle of metabolic and inflammatory disturbances leading to disease. Lipotoxicity, generally defined as an increased concentration of harmful lipids, impairs cellular homeostasis and disrupts tissue function. This is a vast area of study that encompasses many fundamental processes in the cell and involves multiple mechanistic models. Here, we will focus mainly on lipotoxicity as it relates to the integration of metabolic and immune responses, which is critical for health and also plays a role in metabolic diseases (1.Hotamisligil G.S. Inflammation and metabolic disorders.Nature. 2006; 444: 860-867Crossref PubMed Scopus (5708) Google Scholar). Chronic low-grade metabolic inflammation, termed "metaflammation," is considered one of the hallmarks of metabolic diseases such as obesity and diabetes, and it occurs in several metabolic tissues, including adipose tissue, liver, muscle, brain, and gut. Among other potential mechanisms, it is now well-established that immunometabolic pathways are highly responsive to lipids and linked to lipotoxicity (1.Hotamisligil G.S. Inflammation and metabolic disorders.Nature. 2006; 444: 860-867Crossref PubMed Scopus (5708) Google Scholar). Just as lipotoxicity gives rise to metaflammation, alterations in lipid metabolism and signaling can also converge on common immune and stress responses (2.Fu S. Watkins S.M. Hotamisligil G.S. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling.Cell Metab. 2012; 15: 623-634Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar), thus creating vicious pathological cycles that contribute to many diseases. Perturbations in fatty acid and cholesterol fluxes lead to higher representation of harmful lipid classes in cells and in the circulation, especially saturated fatty acids and oxidized cholesterol (Fig. 1). These species have been studied extensively for their effects on cellular function, including inflammatory responses and organ performance. For example, the saturated fatty acid, palmitate, can be imported into cells via fatty acid transport protein 1 (FATP1), and overexpression of FATP1 in the heart leads to lipotoxicity-mediated cardiomyopathy (3.Chiu H.C. Kovacs A. Blanton R.M. Han X. Courtois M. Weinheimer C.J. Yamada K.A. Brunet S. Xu H. Nerbonne J.M. et al.Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy.Circ. Res. 2005; 96: 225-233Crossref PubMed Scopus (330) Google Scholar). Forced exposure to fatty acids can also be a driver for pathologies at other sites or in other metabolic diseases, and the discussion below is predominantly framed in this context. The mechanisms underlying the harmful effects of excess lipid flux are related in part to the impact of lipids on the biophysical properties of cellular organelles. For example, the endoplasmic reticulum (ER), which is one of the major hubs for lipid biosynthesis and esterification, is a critical organelle mediating both metabolic and inflammatory adaptive responses to proteotoxic, nutritional, and energy-related stresses. In the setting of chronic nutrient stress, lipid synthesis is dysregulated in the ER, leading to changes in phospholipid composition of the ER membrane. These changes cause disruption of calcium signaling, prolonged ER stress, and decreased translation of ER-associated proteins (4.Fu S. Yang L. Li P. Hofmann O. Dicker L. Hide W. Lin X. Watkins S.M. Ivanov A.R. Hotamisligil G.S. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity.Nature. 2011; 473: 528-531Crossref PubMed Scopus (621) Google Scholar, 5.Fu S. Fan J. Blanco J. Gimenez-Cassina A. Danial N.N. Watkins S.M. Hotamisligil G.S. Polysome profiling in liver identifies dynamic regulation of endoplasmic reticulum translatome by obesity and fasting.PLoS Genet. 2012; 8: e1002902Crossref PubMed Scopus (37) Google Scholar). Similarly, saturated fatty acids and cholesterol loading increase ER stress and associated cell death (6.Borradaile N.M. Han X. Harp J.D. Gale S.E. Ory D.S. Schaffer J.E. Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death.J. Lipid Res. 2006; 47: 2726-2737Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 7.Wei Y. Wang D. Topczewski F. Pagliassotti M.J. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells.Am. J. Physiol. Endocrinol. Metab. 2006; 291: E275-E281Crossref PubMed Scopus (532) Google Scholar, 8.Feng B. Yao P.M. Li Y. Devlin C.M. Zhang D. Harding H.P. Sweeney M. Rong J.X. Kuriakose G. 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S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction.Science. 2015; 349: 500-506Crossref PubMed Scopus (130) Google Scholar) represents one example of the indirect impact of lipotoxicity on chronic inflammatory processes. Beyond the alteration of organelle function, lipotoxicity can also influence metaflammation and hormone action via direct effects on intracellular signaling pathways. For example, palmitate exposure is implicated in synthesis of diacylglycerols (DAGs) (19.Glass C.K. Olefsky J.M. Inflammation and lipid signaling in the etiology of insulin resistance.Cell Metab. 2012; 15: 635-645Abstract Full Text Full Text PDF PubMed Scopus (519) Google Scholar), which can activate novel protein kinase C (PKC) isoforms (20.Schmitz-Peiffer C. Browne C.L. Oakes N.D. Watkinson A. Chisholm D.J. Kraegen E.W. Biden T.J. Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat.Diabetes. 1997; 46: 169-178Crossref PubMed Google Scholar) (Fig. 1) such as PKC-θ and PKC-ε, which have been linked to T cell activation and LPS responses (21.Coudronniere N. Villalba M. Englund N. Altman A. NF-kappa B activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-theta.Proc. Natl. Acad. Sci. USA. 2000; 97: 3394-3399PubMed Google Scholar, 22.Aksoy E. Amraoui Z. Goriely S. Goldman M. Willems F. Critical role of protein kinase C epsilon for lipopolysaccharide-induced IL-12 synthesis in monocyte-derived dendritic cells.Eur. J. Immunol. 2002; 32: 3040-3049Crossref PubMed Scopus (0) Google Scholar) as well as insulin action and metabolic responses (23.Perry R.J. Samuel V.T. Petersen K.F. Shulman G.I. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes.Nature. 2014; 510: 84-91Crossref PubMed Scopus (638) Google Scholar). While the exact mechanisms underlying these signaling events and the lipid species that engage PKCs remains under debate (23.Perry R.J. Samuel V.T. Petersen K.F. Shulman G.I. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes.Nature. 2014; 510: 84-91Crossref PubMed Scopus (638) Google Scholar, 24.Zechner R. Zimmermann R. Eichmann T.O. Kohlwein S.D. Haemmerle G. Lass A. Madeo F. FAT SIGNALS–lipases and lipolysis in lipid metabolism and signaling.Cell Metab. 2012; 15: 279-291Abstract Full Text Full Text PDF PubMed Scopus (596) Google Scholar), there is strong evidence supporting the involvement of PKCs in both metabolic and inflammatory responses that are relevant to obesity and type 2 diabetes. Palmitate accumulation also leads to ceramide biosynthesis, which can activate inflammatory pathways and inhibit insulin action (Fig. 1). Ceramides inhibit Akt-mediated insulin signaling as well as mitochondrial fatty acid oxidation by disrupting mitochondrial electron transport (25.Stratford S. Hoehn K.L. Liu F. Summers S.A. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B.J. Biol. Chem. 2004; 279: 36608-36615Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar, 26.Turpin S.M. Nicholls H.T. Willmes D.M. Mourier A. Brodesser S. Wunderlich C.M. Mauer J. Xu E. Hammerschmidt P. Bronneke H.S. et al.Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance.Cell Metab. 2014; 20: 678-686Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar, 27.Raichur S. Wang S.T. Chan P.W. Li Y. Ching J. Chaurasia B. Dogra S. Ohman M.K. Takeda K. 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Interestingly, toll-like receptor 4 (TLR4) signaling can also lead to increased expression of ceramide biosynthetic enzymes (30.Holland W.L. Bikman B.T. Wang L.P. Yuguang G. Sargent K.M. Bulchand S. Knotts T.A. Shui G. Clegg D.J. Wenk M.R. et al.Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice.J. Clin. Invest. 2011; 121: 1858-1870Crossref PubMed Scopus (430) Google Scholar), suggesting the importance of this pathway in mediating metaflammation and insulin resistance and the reciprocal and highly integrated operation of lipid and immune signaling pathways (Fig. 1). Finally, lipids can influence cell fate and function by engaging receptors on the cell surface or stress kinases within the cytoplasm. Fatty acids such as palmitate can directly activate inflammatory pathways by increasing TLR4 signaling (31.Lee J.Y. Sohn K.H. Rhee S.H. Hwang D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4.J. Biol. Chem. 2001; 276: 16683-16689Abstract Full Text Full Text PDF PubMed Scopus (909) Google Scholar) and by stimulating signaling molecules such as PKR (10.Nakamura T. Furuhashi M. Li P. Cao H. Tuncman G. Sonenberg N. Gorgun C.Z. Hotamisligil G.S. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis.Cell. 2010; 140: 338-348Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar) (Fig. 1). In response to harmful lipids such as palmitate and oxidized cholesterol, PKR can activate JNK, leading to engagement of downstream transcription factor activator protein 1 (AP-1) and expression of genes that mediate inflammation and apoptosis and promote inflammasome activity (32.Takada Y. Ichikawa H. Pataer A. Swisher S. Aggarwal B.B. 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Scruggs B.S. Sidhu R. Brookheart R.T. Listenberger L.L. Behlke M.A. Ory D.S. Schaffer J.E. Small nucleolar RNAs U32a, U33, and U35a are critical mediators of metabolic stress.Cell Metab. 2011; 14: 33-44Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). Interestingly, PKR is the only kinase that also has direct double stranded RNA binding activity, and snoRNAs are enriched in PKR immunoprecipitates after palmitate treatment, suggesting that palmitate sensing by PKR may involve direct binding of snoRNAs to PKR for its activation in the metabolic disease context (36.Youssef O.A. Safran S.A. Nakamura T. Nix D.A. Hotamisligil G.S. Bass B.L. Potential role for snoRNAs in PKR activation during metabolic stress.Proc. Natl. Acad. Sci. USA. 2015; 112: 5023-5028Crossref PubMed Scopus (73) Google Scholar). How snoRNAs are involved in signaling lipotoxicity at the molecular level is yet unclear, but cells with impaired ability to produce snoRNAs are resistant to lipotoxicity-induced ER stress and death (37.Scruggs B.S. Michel C.I. Ory D.S. Schaffer J.E. SmD3 regulates intronic noncoding RNA biogenesis.Mol. Cell. Biol. 2012; 32: 4092-4103Crossref PubMed Scopus (16) Google Scholar), indicating the potential of snoRNAs serving as mediators of broad lipotoxic responses. This is one of the most interesting emerging areas of research related to mechanisms of lipotoxicity and metabolic regulation. Continuous cycles of nutritional exposures and changing environmental factors require integrated metabolic, stress, and immune responses in many critical organs. Under chronic energy and substrate excess, metabolic stress is unresolved, yielding maladaptive outcomes, such as unresolved inflammation, impaired hormone action, lipid accumulation, and loss of function. Here, we will not discuss specific conditions such as insulin resistance, fatty liver disease, and cardiovascular pathologies, which are covered in detail in excellent recent reviews (2.Fu S. Watkins S.M. Hotamisligil G.S. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling.Cell Metab. 2012; 15: 623-634Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar, 19.Glass C.K. Olefsky J.M. Inflammation and lipid signaling in the etiology of insulin resistance.Cell Metab. 2012; 15: 635-645Abstract Full Text Full Text PDF PubMed Scopus (519) Google Scholar, 38.Rosen E.D. Spiegelman B.M. What we talk about when we talk about fat.Cell. 2014; 156: 20-44Abstract Full Text Full Text PDF PubMed Scopus (1168) Google Scholar, 39.Goldberg I.J. Trent C.M. Schulze P.C. Lipid metabolism and toxicity in the heart.Cell Metab. 2012; 15: 805-812Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, 40.Samuel V.T. Shulman G.I. 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During times of excess nutrient availability, LDs act as a depot for excess fatty acids and cholesterol that are otherwise harmful to the cells (43.Farese Jr., R.V. Walther T.C. Lipid droplets finally get a little R-E-S-P-E-C-T.Cell. 2009; 139: 855-860Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar). In higher organisms, this can occur in all cells, but the most dramatic example is the adipose tissue, a specialized organ for lipid deposition. In the setting of increased metabolic demand, adipocytes hydrolyze neutralized lipids in LDs through lipolysis, liberating fatty acids for use in other tissues, feeding mitochondrial fatty acid oxidation pathways, and creating metabolic intermediates that serve as substrates or signaling molecules (24.Zechner R. Zimmermann R. Eichmann T.O. Kohlwein S.D. Haemmerle G. Lass A. Madeo F. 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