Oxidized linoleic acid metabolites induce liver mitochondrial dysfunction, apoptosis, and NLRP3 activation in mice

Abstract

Circulating oxidized linoleic acid (LA) metabolites (OXLAMs) are increased in patients with nonalcoholic steatohepatitis (NASH) and their levels correlate with disease severity. However, the mechanisms by which OXLAMs contribute to NASH development are incompletely understood. We tested the hypothesis that LA or OXLAMs provided directly through the diet are involved in the development of hepatic injury. C57BL/6 mice were fed an isocaloric high-fat diet containing low LA, high LA, or OXLAMs for 8 weeks. The livers of OXLAM-fed mice showed lower triglyceride concentrations, but higher FA oxidation and lipid peroxidation in association with increased oxidative stress. OXLAM-induced mitochondrial dysfunction was associated with reduced Complex I protein and hepatic ATP levels, as well as increased mitochondrial biogenesis and cytoplasmic mitochondrial DNA. Oxidative stress increased thioredoxin-interacting protein (TXNIP) in the liver and stimulated the activation of mitochondrial apoptosis signal-regulating kinase 1 (ASK1) leading to apoptosis. We also found increased levels of NOD-like receptor protein 3 (NLRP3) inflammasome components and Caspase-1 activation in the livers of OXLAM-fed mice. In vitro, OXLAMs induced hepatocyte cell death, which was partly dependent on Caspase-1 activation. This study identified key mechanisms by which dietary OXLAMs contribute to NASH development, including mitochondrial dysfunction, hepatocyte cell death, and NLRP3 inflammasome activation. Circulating oxidized linoleic acid (LA) metabolites (OXLAMs) are increased in patients with nonalcoholic steatohepatitis (NASH) and their levels correlate with disease severity. However, the mechanisms by which OXLAMs contribute to NASH development are incompletely understood. We tested the hypothesis that LA or OXLAMs provided directly through the diet are involved in the development of hepatic injury. C57BL/6 mice were fed an isocaloric high-fat diet containing low LA, high LA, or OXLAMs for 8 weeks. The livers of OXLAM-fed mice showed lower triglyceride concentrations, but higher FA oxidation and lipid peroxidation in association with increased oxidative stress. OXLAM-induced mitochondrial dysfunction was associated with reduced Complex I protein and hepatic ATP levels, as well as increased mitochondrial biogenesis and cytoplasmic mitochondrial DNA. Oxidative stress increased thioredoxin-interacting protein (TXNIP) in the liver and stimulated the activation of mitochondrial apoptosis signal-regulating kinase 1 (ASK1) leading to apoptosis. We also found increased levels of NOD-like receptor protein 3 (NLRP3) inflammasome components and Caspase-1 activation in the livers of OXLAM-fed mice. In vitro, OXLAMs induced hepatocyte cell death, which was partly dependent on Caspase-1 activation. This study identified key mechanisms by which dietary OXLAMs contribute to NASH development, including mitochondrial dysfunction, hepatocyte cell death, and NLRP3 inflammasome activation. Linoleic acid (LA) is the most abundant n-6 PUFA in Western diets and cannot be synthesized de novo. Therefore, LA belongs to the group of essential FAs sourced exclusively from the diet and detectable in blood and other tissues, such as the liver. In the body, LA is converted into arachidonic acid, a precursor of important eicosanoids with pro-inflammatory, atherogenic, and pro-thrombotic properties, as well as mediators with anti-inflammatory, pro-resolving, and vasodilatory properties (e.g., lipoxins, PGI2) (1.Serhan C.N. Chiang N. Dalli J. Levy B.D. Lipid mediators in the resolution of inflammation.Cold Spring Harb. Perspect. Biol. 2014; 7: a016311PubMed Google Scholar). LA itself can also be enzymatically oxidized via the actions of 12/15 lipoxygenase, cyclooxygenases, or the CYP450 enzyme family (2.Engels F. Willems H. Nijkamp F.P. Cyclooxygenase-catalyzed formation of 9-hydroxylinoleic acid by guinea pig alveolar macrophages under non-stimulated conditions.FEBS Lett. 1986; 209: 249-253Crossref PubMed Scopus (46) Google Scholar, 3.Reinaud O. Delaforge M. Boucher J.L. Rocchiccioli F. Mansuy D. Oxidative metabolism of linoleic acid by human leukocytes.Biochem. Biophys. Res. Commun. 1989; 161: 883-891Crossref PubMed Scopus (57) Google Scholar), or via free radical-mediated oxidation in response to oxidative stress (4.Liu W. Yin H. Akazawa Y.O. Yoshida Y. Niki E. Porter N.A. Ex vivo oxidation in tissue and plasma assays of hydroxyoctadecadienoates: Z,E/E,E stereoisomer ratios.Chem. Res. Toxicol. 2010; 23: 986-995Crossref PubMed Scopus (57) Google Scholar) leading to the formation of epoxy- and mono-, di-, and tri-hydroxy FAs. These oxidized LA metabolites (OXLAMs), including 9- and 13-HODE and 9- and 13-oxo-octadecadienoic acid, are abundant in the liver and have been reported to promote liver damage in mice consuming alcohol (5.Feldstein A.E. Lopez R. Tamimi T.A. Yerian L. Chung Y.M. Berk M. Zhang R. McIntyre T.M. Hazen S.L. Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.J. Lipid Res. 2010; 51: 3046-3054Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 6.Warner D.R. Liu H. Miller M.E. Ramsden C.E. Gao B. Feldstein A.E. Schuster S. McClain C.J. Kirpich I.A. Dietary linoleic acid and its oxidized metabolites exacerbate liver injury caused by ethanol via induction of hepatic proinflammatory response in mice.Am. J. Pathol. 2017; 187: 2232-2245Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). Nonalcoholic fatty liver disease (NAFLD) refers to a spectrum of histological abnormalities in the liver spanning from isolated steatosis (also referred to as NAFL) to nonalcoholic steatohepatitis (NASH), with the latter being characterized by steatosis, hepatocellular damage, and inflammatory changes with varying degrees of scarring and/or fibrosis. NASH is a serious condition, as approximately 25% of these patients progress to cirrhosis and its feared complications of portal hypertension, liver failure, and hepatocellular carcinoma (7.Bedossa P. Pathology of non-alcoholic fatty liver disease.Liver Int. 2017; 37: 85-89Crossref PubMed Scopus (176) Google Scholar). NAFLD is currently the most common cause of chronic liver disease in both children and adults worldwide with an estimated global prevalence of 25% and is strongly associated with obesity and insulin resistance (8.Younossi Z.M. Koenig A.B. Abdelatif D. Fazel Y. Henry L. Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology. 2016; 64: 73-84Crossref PubMed Scopus (5294) Google Scholar, 9.Marengo A. Jouness R.I. Bugianesi E. Progression and natural history of nonalcoholic fatty liver disease in adults.Clin. Liver Dis. 2016; 20: 313-324Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). A reduction in n-6 PUFA consumption reduced OXLAM synthesis in humans (10.Ramsden C.E. Ringel A. Feldstein A.E. Taha A.Y. MacIntosh B.A. Hibbeln J.R. Majchrzak-Hong S.F. Faurot K.R. Rapoport S.I. Cheon Y. et al.Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans.Prostaglandins Leukot. Essent. Fatty Acids. 2012; 87: 135-141Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar) and protected mice against high-fat diet-induced NASH (11.Lazic M. Inzaugarat M.E. Povero D. Zhao I.C. Chen M. Nalbandian M. Miller Y.I. Chernavsky A.C. Feldstein A.E. Sears D.D. Reduced dietary omega-6 to omega-3 fatty acid ratio and 12/15-lipoxygenase deficiency are protective against chronic high fat diet-induced steatohepatitis.PLoS One. 2014; 9: e107658Crossref PubMed Scopus (42) Google Scholar). Modern industrialized diets contain substantial amounts of thermally stressed processed food products that are rich in OXLAMs (12.Dobarganes C. Marquez-Ruiz G. Oxidized fats in foods.Curr. Opin. Clin. Nutr. Metab. Care. 2003; 6: 157-163Crossref PubMed Scopus (105) Google Scholar). In humans, circulating OXLAMs strongly correlate with liver histopathology, such as inflammation, fibrosis, and steatosis (5.Feldstein A.E. Lopez R. Tamimi T.A. Yerian L. Chung Y.M. Berk M. Zhang R. McIntyre T.M. Hazen S.L. Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.J. Lipid Res. 2010; 51: 3046-3054Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar); and in rats administered oxidized corn oil, circulating OXLAMs were shown to cell activation H. M. F. M. S. M. A. et fatty hepatic A hypothesis to steatohepatitis.J. Full Text Full Text PDF PubMed Scopus Google Scholar). a for of NASH in humans circulating OXLAM levels been as being the for NASH (5.Feldstein A.E. Lopez R. Tamimi T.A. Yerian L. Chung Y.M. Berk M. Zhang R. McIntyre T.M. Hazen S.L. Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.J. Lipid Res. 2010; 51: 3046-3054Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar). oxidative stress is as a key to hepatocyte injury NASH development, the of OXLAMs directly via a high-fat including their of The study isocaloric high-fat diets that were to in their LA or OXLAM LA, high LA, and an diet in to their on the development of liver mitochondrial dysfunction, and in a NASH induced by a high-fat diet We to OXLAMs directly the oxidative stress response and by the of mitochondrial dysfunction and NOD-like receptor protein 3 (NLRP3) inflammasome activation. mice were from mice were fed a diet for 1 to 8 of mice were in isocaloric diet of and fat and to contain low LA of high LA of or OXLAMs of OXLAMs from thermally stressed corn mice were fed for 8 weeks. were by The food was mice free to food and the The of and the and in the LA low LA LA LA low LA LA low LA low LA LA LA LA low LA LA low LA LA low LA LA low LA LA low LA LA low LA low LA LA low are as were by and was LA low LA OXLAMs low in a are as were by and was stressed corn was by of corn from a in a in an for approximately with of the The and corn was with the diets in the in that the corn in increased dietary a of of the diets was into with and and to OXLAM by as reported C.E. M. Y. D. J. B.D. Taha A.Y. of oxidized fatty in and 2017; PubMed Scopus Google Scholar). In of the diets were in containing acid, and of containing of and in for The were to and to C.E. M. Y. D. J. B.D. Taha A.Y. of oxidized fatty in and 2017; PubMed Scopus Google Scholar). We metabolites that 8 mice were for being were via Liver tissue was and were in for in on and in or in and were in and were for The of was on the of the NAFLD by M. C. Liu A. et and of a histological for nonalcoholic fatty liver PubMed Scopus Google Scholar) and from to 3 on inflammatory study liver cell death, was the in apoptosis and were in were for and for The was to a and for was was to the were in containing and of protein were on to in and with were with were with the or and a was with and to or apoptosis signal-regulating kinase 1 (ASK1) protein (TXNIP) protein containing a to and were was isolated from liver tissue and as A. A. A. Feldstein A.E. NLRP3 inflammasome activation in hepatocyte liver inflammation, and in 2014; PubMed Scopus Google Scholar). The of the for are provided in liver tissue was in 3 and with to the of of liver of Liver triglyceride was the to was in liver tissue the acid and was to protein of of The protein were by Western and the of was ATP levels were the ATP to was with the was the blood and tissue to A. P. of mitochondrial of mitochondrial 2016; PubMed Scopus Google Scholar). in mitochondrial have been shown to be associated with mitochondrial dysfunction A. P. of mitochondrial of mitochondrial 2016; PubMed Scopus Google Scholar, A. mitochondrial a of mitochondrial PubMed Scopus Google Scholar). was by the of et R. A. A. P. as a of and Biophys. Res. Commun. PubMed Scopus Google Scholar). for and were to the products from the of cytoplasmic liver tissue from and a the mitochondrial for tissue The for tissue with of the was The was for of by the was isolated from the blood and tissue The of in the was and was for the The mitochondrial to ratio was the the was as Caspase-1 in liver tissue the Caspase-1 to were by and the were by and on the of isolated from mice were in with and were in with and and were and were in or in were on and were in ethanol and to the in and for Caspase-1 activation was by Caspase-1 1 OXLAM was as a was for the to the was the to the We as to cell were with The was for were and were by the and are as C57BL/6 mice were fed with isocaloric high-fat diets containing from fat with low LA, high LA, or low LA OXLAMs from thermally stressed corn study showed that the of LA in the diet was higher in the high LA group with the low LA and OXLAM diet LA of LA low LA of LA of However, LA in the OXLAM diet was lower in the low LA OXLAM was higher in the OXLAM diet with the low and high LA diet OXLAMs in low LA high LA A of metabolites in the of the mice is in the diet a lower low the low LA and high LA 8 the mice were and the livers were liver high and liver to ratio of were higher in the OXLAM-fed group with the low LA and high LA high Liver that the OXLAM-fed mice a lower steatosis the low LA and high LA However, was increased in the OXLAM group with the low LA group the histological a the hepatic and the of key for FA metabolism The livers of mice fed the OXLAM diet of a lower the low LA group mice that the high LA diet a lower liver fat with the low LA as shown by histological steatosis and This was associated with a of in the an that been to n-6 A. M. of and by fatty Lipid Res. Full Text PDF PubMed Google Scholar). the lower levels in OXLAM-fed mice were to reduced Therefore, OXLAM-fed mice showed in FA a key and of lipid was in mice fed a high LA diet or an OXLAM diet with the low LA activation the and of FAs N. J. and as of lipid PubMed Scopus Google Scholar). In with found the of a key enzyme of mitochondrial G. L. of and for the and fatty acid 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), I increased in mice fed the high LA or OXLAM diet with the low LA group the induction of was for 1 the key enzyme of FA OXLAM-fed mice showed a in with low mice high LA with low LA FA oxidation is involved in but is directly to the of in increased levels of and fatty acid oxidation in Biophys. PubMed Scopus (46) Google Scholar). The a of lipid was in the liver protein from OXLAM-fed mice The protein and protein and cell G. S. M. C. A. C. C. A. et of in human PubMed Scopus Google Scholar). with low LA mice fed the OXLAM diet showed a of protein of of lipid peroxidation and oxidative were increased in mice that the OXLAM diet with the high LA and low LA the consumption of high LA of lipid peroxidation with the low LA a protein of increased levels J. of protein (TXNIP) in oxidative apoptosis and PubMed Scopus Google Scholar), was both the and protein in mice fed the high LA and OXLAM diets in high LA OXLAM with low LA changes in and oxidative stress in the liver. are to in the is through and the other is from in the mitochondrial oxidative in the We found in the hepatic the which to that mitochondrial is the of oxidative stress in OXLAM-fed mice. the increased lipid peroxidation and levels were associated with in mitochondrial and the on the of a of caused by the of of the precursor such as a of the Complex I been shown to mitochondrial S. H. R. the of in PubMed Scopus Google Scholar). the of precursor the protein of and found to be reduced in the OXLAM-fed group with low LA, the high LA diet showed but with low LA, We the ATP in to reduced Complex I levels to in the fed an diet a lower hepatic ATP with the low LA group the ATP levels in the high LA group were reduced ATP levels were also associated with increased mitochondrial by increased of protein and low or and levels were found in the low LA both were in the livers of mice fed the OXLAM diet with low the LA group are to the response and mitochondrial biogenesis as an response A. mitochondrial a of mitochondrial PubMed Scopus Google Scholar). OXLAM-fed mice showed in mitochondrial the to as of mitochondrial that increased the ratio in the liver by with low LA which was associated with increased of mitochondrial A is involved in mitochondrial and and of human mitochondrial Biol. PubMed Scopus Google Scholar). In to increased mitochondrial also levels of cytoplasmic with the low LA a of from the into the and mitochondrial OXLAM-induced mitochondrial dysfunction and the of in liver cell death, the of in liver and found an increased of with the low LA and high LA However, changes were found in levels the LA hepatocellular or levels with the low LA group can be by and oxidative apoptosis by mitochondrial cell A. S. Y. S. H. of apoptosis signal-regulating kinase 1 apoptosis by the Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). We to OXLAM-induced oxidative stress and mitochondrial protein that OXLAM-induced oxidative stress increased protein levels in the in association with the activation of a of We that with the low LA and high LA increased into the under oxidative stress its and activation in with low LA, However, mitochondrial protein levels in the or high mice. protein of the mitochondrial cell such as and were also in OXLAM-fed mice with the low LA FAs to the group of inflammasome to study OXLAMs are also to the NLRP3 inflammasome We also to OXLAM-induced hepatocyte damage be dependent on increased inflammasome activation. showed that livers from OXLAM-fed mice have increased NLRP3 inflammasome activation with the low LA and high LA as by protein levels of NLRP3 inflammasome such as and with low as well as the with the low LA group LA showed increased protein levels in the activation of and with the low LA group LA low LA, in the liver activation of and Caspase-1 was in liver and was found to be higher in the livers of OXLAM-fed mice with the low LA and high LA to OXLAMs on stimulated and with OXLAMs and and their on cell We found in reduced in and reduced in and in study increased hepatocyte damage in OXLAM-fed mice be dependent on increased inflammasome and from mice with OXLAMs and and that the cell in is partly dependent on as the reduced the cell in was protective in in other being involved in cell were found in from mice showed cell with OXLAMs with These that NLRP3 inflammasome activation is partly directly by the consumption of directly cell with NLRP3 inflammasome activation. The of the study was to the consumption of dietary OXLAMs to hepatocyte damage and oxidative stress in mice consuming a high-fat fed mice for 8 with isocaloric high-fat diets containing amounts of LA and or with for the the of OXLAMs in the induction of mitochondrial dysfunction, liver cell death, and NLRP3 inflammasome activation lipid metabolism with apoptosis and the response We that mice a diet with OXLAMs have increased hepatic lipid peroxidation associated with increased oxidative stress and as well as NLRP3 inflammasome and activation. showed that a diet rich in LA the plasma reduces hepatic and hepatic FA but is to oxidative damage, inflammation, and NLRP3 inflammasome activation. However, cannot that with high LA as of mitochondrial dysfunction, such as reduced mitochondrial Complex 1 protein lower ATP levels, and increased protein levels, were in mice fed the high LA In a reported that the of ethanol and a diet rich in LA liver damage D.R. Liu H. Miller M.E. Ramsden C.E. Gao B. Feldstein A.E. Schuster S. McClain C.J. Kirpich I.A. Dietary linoleic acid and its oxidized metabolites exacerbate liver injury caused by ethanol via induction of hepatic proinflammatory response in mice.Am. J. Pathol. 2017; 187: 2232-2245Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar), that a high of LA to In the found that mice fed an diet showed increased levels of in the are to be of oxidative stress and both as and as products of lipid peroxidation including changes in and P. D. A. with and or PubMed Scopus Google Scholar, N. A. M. S. of protein PubMed Scopus Google Scholar). We showed that dietary OXLAMs FA via increased that OXLAMs directly through such as or other M. O. G. S. N. of free in Res. PubMed Scopus Google Scholar). et F. M. P. S. is a fatty acid that mitochondrial oxidation in and against fatty Lipid Res. 2010; 51: Full Text Full Text PDF PubMed Scopus Google Scholar) and et Y. Y. G. E. A. J. B. M. S. 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Dietary linoleic acid and its oxidized metabolites exacerbate liver injury caused by ethanol via induction of hepatic proinflammatory response in mice.Am. J. Pathol. 2017; 187: 2232-2245Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). However, the reported to oxidized in to be with as is a and the of of dietary be to the of OXLAM the of other OXLAMs found in the diet and and tri-hydroxy and mice are to or diet liver or disease and metabolism be involved in their of OXLAMs a oxidative in in the and NASH and hepatocellular carcinoma We that the study an important for dietary OXLAMs in mitochondrial and NLRP3 inflammasome activation. 1 protein containing a apoptosis signal-regulating kinase 1 linoleic acid mitochondrial mitochondrial mitochondrial to ratio nonalcoholic fatty liver disease nonalcoholic steatohepatitis NOD-like receptor protein 3 oxidized linoleic acid mitochondrial A triglyceride thioredoxin-interacting protein protein