BACKGROUND: Resident macrophages (Kupffer cells, KCs) in the liver can undergo both pro- or anti-inflammatory activation pathway and exert either beneficiary or detrimental effects on liver metabolism. Until now, their role in the metabolically dysfunctional state of steatosis remains enigmatic. Aim of our study was to characterize the role of KCs in relation to the onset of hepatic insulin resistance induced by a high-fat (HF) diet rich in monounsaturated fatty acids. METHODS: Male Wistar rats were fed either standard (SD) or high-fat (HF) diet for 4 weeks. Half of the animals were subjected to the acute GdCl3 treatment 24 and 72 hrs prior to the end of the experiment in order to induce the reduction of KCs population. We determined the effect of HF diet on activation status of liver macrophages and on the changes in hepatic insulin sensitivity and triacylglycerol metabolism imposed by acute KCs depletion by GdCl3. RESULTS: We found that a HF diet rich in MUFA itself triggers an alternative but not the classical activation program in KCs. In a steatotic, but not in normal liver, a reduction of the KCs population was associated with a decrease of alternative activation and with a shift towards the expression of pro-inflammatory activation markers, with the increased autophagy, elevated lysosomal lipolysis, increased formation of DAG, PKCε activation and marked exacerbation of HF diet-induced hepatic insulin resistance. CONCLUSIONS: We propose that in the presence of a high MUFA content the population of alternatively activated resident liver macrophages may mediate beneficial effects on liver insulin sensitivity and alleviate the metabolic disturbances imposed by HF diet feeding and steatosis. Our data indicate that macrophage polarization towards an alternative state might be a useful strategy for treating type 2 diabetes.

Department of Metabolism and Diabetes Institute for Clinical and Experimental Medicine Videnska 1958 9 Prague 14021 Czech Republic

Zobrazit více v PubMed

Rector RS, Thyfault JP, Wei Y, Ibdah JA. Non-alcoholic fatty liver disease and the metabolic syndrome: an update. World J Gastroenterol. 2008;14:185–192. doi: 10.3748/wjg.14.185. PubMed DOI PMC

Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259:87–91. doi: 10.1126/science.7678183. PubMed DOI

Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164:6166–6173. PubMed

Goerdt S, Orfanos CE. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity. 1999;10:137–142. doi: 10.1016/S1074-7613(00)80014-X. PubMed DOI

Fessler MB, Rudel LL, Brown JM. Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome. Curr Opin Lipidol. 2009;20:379–385. doi: 10.1097/MOL.0b013e32832fa5c4. PubMed DOI PMC

Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature. 2007;447:1116–1120. doi: 10.1038/nature05894. PubMed DOI PMC

Rivellese AA, De Natale C, Lilli S. Type of dietary fat and insulin resistance. Ann N Y Acad Sci. 2002;967:329–335. PubMed

Brousseau ME, Schaefer EJ. Diet and coronary heart disease: clinical trials. Curr Atheroscler Rep. 2000;2:487–493. doi: 10.1007/s11883-000-0048-6. PubMed DOI

Munford RS, Hall CL. Detoxification of bacterial lipopolysaccharides (endotoxins) by a human neutrophil enzyme. Science. 1986;234:203–205. doi: 10.1126/science.3529396. PubMed DOI

Qureshi N, Takayama K, Kurtz R. Diphosphoryl lipid A obtained from the nontoxic lipopolysaccharide of Rhodopseudomonas sphaeroides is an endotoxin antagonist in mice. Infect Immun. 1991;59:441–444. PubMed PMC

Galgani JE, Uauy RD, Aguirre CA, Diaz EO. Effect of the dietary fat quality on insulin sensitivity. Br J Nutr. 2008;100:471–479. doi: 10.1017/S0007114508894408. PubMed DOI

Gillingham LG, Harris-Janz S, Jones PJ. Dietary monounsaturated fatty acids are protective against metabolic syndrome and cardiovascular disease risk factors. Lipids. 2011;46:209–228. doi: 10.1007/s11745-010-3524-y. PubMed DOI

Lopez S, Bermudez B, Abia R, Muriana FJ. The influence of major dietary fatty acids on insulin secretion and action. Curr Opin Lipidol. 2010;21:15–20. doi: 10.1097/MOL.0b013e3283346d39. PubMed DOI

Bourlier V, Bouloumie A. Role of macrophage tissue infiltration in obesity and insulin resistance. Diabetes Metab. 2009;35:251–260. doi: 10.1016/j.diabet.2009.05.001. PubMed DOI

Caballero F, Fernandez A, Matias N, Martinez L, Fucho R, Elena M, Caballeria J, Morales A, Fernandez-Checa JC, Garcia-Ruiz C. Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-L-methionine and glutathione. J Biol Chem. 2010;285:18528–18536. doi: 10.1074/jbc.M109.099333. PubMed DOI PMC

Sheth K, Bankey P. The liver as an immune organ. Curr Opin Crit Care. 2001;7:99–104. doi: 10.1097/00075198-200104000-00008. PubMed DOI

Sun Z, Wada T, Maemura K, Uchikura K, Hoshino S, Diehl AM, Klein AS. Hepatic allograft-derived Kupffer cells regulate T cell response in rats. Liver Transpl. 2003;9:489–497. doi: 10.1053/jlts.2003.50091. PubMed DOI

Parker GA, Picut CA. Liver immunobiology. Toxicol Pathol. 2005;33:52–62. doi: 10.1080/01926230590522365. PubMed DOI

Canbay A, Feldstein AE, Higuchi H, Werneburg N, Grambihler A, Bronk SF, Gores GJ. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology. 2003;38:1188–1198. doi: 10.1053/jhep.2003.50472. PubMed DOI

Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev. 2009;89:1269–1339. doi: 10.1152/physrev.00027.2008. PubMed DOI

Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23–35. doi: 10.1038/nri978. PubMed DOI

Herbert DR, Holscher C, Mohrs M, Arendse B, Schwegmann A, Radwanska M, Leeto M, Kirsch R, Hall P, Mossmann H, Claussen B, Forster I, Brombacher F. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity. 2004;20:623–635. doi: 10.1016/S1074-7613(04)00107-4. PubMed DOI

Clementi AH, Gaudy AM, van Rooijen N, Pierce RH, Mooney RA. Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling. Biochim Biophys Acta. 2009;1792:1062–1072. PubMed PMC

Rai RM, Loffreda S, Karp CL, Yang SQ, Lin HZ, Diehl AM. Kupffer cell depletion abolishes induction of interleukin-10 and permits sustained overexpression of tumor necrosis factor alpha messenger RNA in the regenerating rat liver. Hepatology. 1997;25:889–895. doi: 10.1002/hep.510250417. PubMed DOI

Lanthier N, Molendi-Coste O, Horsmans Y, van Rooijen N, Cani PD, Leclercq IA. Kupffer cell activation is a causal factor for hepatic insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2010;298:G107–116. doi: 10.1152/ajpgi.00391.2009. PubMed DOI

Neyrinck AM, Cani PD, Dewulf EM, De Backer F, Bindels LB, Delzenne NM. Critical role of Kupffer cells in the management of diet-induced diabetes and obesity. Biochem Biophys Res Commun. 2009;385:351–356. doi: 10.1016/j.bbrc.2009.05.070. PubMed DOI

Committee for the Update of the Guide for the Care and Use of laboratory Animals. NIH Guide to the Care and Use of Laboratory Animals. 8. National Academies Press: NW Washington; 2011.

Brinkhof B, Spee B, Rothuizen J, Penning LC. Development and evaluation of canine reference genes for accurate quantification of gene expression. Anal Biochem. 2006;356:36–43. doi: 10.1016/j.ab.2006.06.001. PubMed DOI

Cahova M, Dankova H, Palenickova E, Papackova Z, Kazdova L. The autophagy-lysosomal pathway is involved in TAG degradation in the liver: the effect of high-sucrose and high-fat diet. Folia Biol (Praha) 2010;56:173–182. PubMed

Belfrage P, Vaughan M. Simple liquid-liquid partition system for isolation of labeled oleic acid from mixtures with glycerides. J Lipid Res. 1969;10:341–344. PubMed

Rubinsztein DC, Cuervo AM, Ravikumar B, Sarkar S, Korolchuk V, Kaushik S, Klionsky DJ. In search of an "autophagometer". Autophagy. 2009;5:585–589. doi: 10.4161/auto.5.5.8823. PubMed DOI

Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957;226:497–509. PubMed

Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ. Autophagy regulates lipid metabolism. Nature. 2009;458:1131–1135. doi: 10.1038/nature07976. PubMed DOI PMC

Seglen PO, Solheim AE. Conversion of dense lysosomes into light lysosomes during hepatocytic autophagy. Exp Cell Res. 1985;157:550–555. doi: 10.1016/0014-4827(85)90141-7. PubMed DOI

Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004;279:32345–32353. doi: 10.1074/jbc.M313478200. PubMed DOI

Roberts RA, Ganey PE, Ju C, Kamendulis LM, Rusyn I, Klaunig JE. Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol Sci. 2007;96:2–15. PubMed

Andres D, Sanchez-Reus I, Bautista M, Cascales M. Depletion of Kupffer cell function by gadolinium chloride attenuates thioacetamide-induced hepatotoxicity. Expression of metallothionein and HSP70. Biochem Pharmacol. 2003;66:917–926. doi: 10.1016/S0006-2952(03)00443-X. PubMed DOI

Muriel P, Escobar Y. Kupffer cells are responsible for liver cirrhosis induced by carbon tetrachloride. J Appl Toxicol. 2003;23:103–108. doi: 10.1002/jat.892. PubMed DOI

Zhong Z, Connor HD, Mason RP, Qu W, Gao W, Lemasters JJ, Thurman RG. Role of Kupffer cells in reperfusion injury in fat-loaded livers from ethanol-treated rats. J Pharmacol Exp Ther. 1995;275:1512–1517. PubMed

Tsung A, Hoffman RA, Izuishi K, Critchlow ND, Nakao A, Chan MH, Lotze MT, Geller DA, Billiar TR. Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. J Immunol. 2005;175:7661–7668. PubMed

Prins HA, Meijer C, Boelens PG, Diks J, Holtz R, Masson S, Daveau M, Meijer S, Scotte M, van Leeuwen PA. Kupffer cell-depleted rats have a diminished acute-phase response following major liver resection. Shock. 2004;21:561–565. doi: 10.1097/01.shk.0000126649.96850.36. PubMed DOI

Ellett JD, Atkinson C, Evans ZP, Amani Z, Balish E, Schmidt MG, van Rooijen N, Schnellmann RG, Chavin KD. Murine Kupffer cells are protective in total hepatic ischemia/reperfusion injury with bowel congestion through IL-10. J Immunol. 2010;184:5849–5858. doi: 10.4049/jimmunol.0902024. PubMed DOI PMC

Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ, Scott DK, O'Doherty RM. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes. 2010;59:347–357. doi: 10.2337/db09-0016. PubMed DOI PMC

Cintra DE, Pauli JR, Araujo EP, Moraes JC, de Souza CT, Milanski M, Morari J, Gambero A, Saad MJ, Velloso LA. Interleukin-10 is a protective factor against diet-induced insulin resistance in liver. J Hepatol. 2008;48:628–637. doi: 10.1016/j.jhep.2007.12.017. PubMed DOI

Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–1830. PubMed PMC

Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, Barrett T, Kim JK, Davis RJ. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science. 2008;322:1539–1543. doi: 10.1126/science.1160794. PubMed DOI PMC

Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116:3015–3025. doi: 10.1172/JCI28898. PubMed DOI PMC

Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JE, van Rooijen N, Staels B, Kersten S, Muller M. Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology. 2010;51:511–522. doi: 10.1002/hep.23337. PubMed DOI

Kewalramani G, Fink LN, Asadi F, Klip A. Palmitate-activated macrophages confer insulin resistance to muscle cells by a mechanism involving protein kinase C theta and epsilon. PLoS One. 2011;6:e26947. doi: 10.1371/journal.pone.0026947. PubMed DOI PMC

Bilan PJ, Samokhvalov V, Koshkina A, Schertzer JD, Samaan MC, Klip A. Direct and macrophage-mediated actions of fatty acids causing insulin resistance in muscle cells. Arch Physiol Biochem. 2009;115:176–190. doi: 10.1080/13813450903079314. PubMed DOI

Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011;12:408–415. doi: 10.1038/ni.2022. PubMed DOI PMC

Oliver E, McGillicuddy FC, Harford KA, Reynolds CM, Phillips CM, Ferguson JF, Roche HM. Docosahexaenoic acid attenuates macrophage-induced inflammation and improves insulin sensitivity in adipocytes-specific differential effects between LC n-3 PUFA. J Nutr Biochem. 2011. http://dx.doi.org/10.1016./j.bbr.2011.03.031 PubMed DOI

Mullen A, Loscher CE, Roche HM. Anti-inflammatory effects of EPA and DHA are dependent upon time and dose-response elements associated with LPS stimulation in THP-1-derived macrophages. J Nutr Biochem. 2010;21:444–450. doi: 10.1016/j.jnutbio.2009.02.008. PubMed DOI

Papackova Z, Palenickova E, Dankova H, Cahova M, Kazdova L. The role of tissue macrophages in the development of metabolic syndrome associated dysorders: the effect of high fat diet and the fatty acid composition) Cas Lek Ces. 2011;150:185–193.

Lanthier N, Molendi-Coste O, Cani PD, van Rooijen N, Horsmans Y, Leclercq IA. Kupffer cell depletion prevents but has no therapeutic effect on metabolic and inflammatory changes induced by a high-fat diet. FASEB J. 2011;25:4301–4311. doi: 10.1096/fj.11-189472. PubMed DOI

Monetti M, Levin MC, Watt MJ, Sajan MP, Marmor S, Hubbard BK, Stevens RD, Bain JR, Newgard CB, Farese RV Sr, Hevener AL, Farese RV Jr. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab. 2007;6:69–78. doi: 10.1016/j.cmet.2007.05.005. PubMed DOI

Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, Still CD, Gerhard GS, Han X, Dziura J, Petersen KF, Samuel VT, Shulman GI. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci USA. 2011;108:16381–16385. doi: 10.1073/pnas.1113359108. PubMed DOI PMC

Bouhlel MA, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 2007;6:137–143. doi: 10.1016/j.cmet.2007.06.010. PubMed DOI

Harris J. Autophagy and cytokines. Cytokine. 2011;56:140–144. doi: 10.1016/j.cyto.2011.08.022. PubMed DOI

Hayase K, Tappel AL. Specificity and other properties of lysosomal lipase of rat liver. J Biol Chem. 1970;245:169–175. PubMed

Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB J. 1995;9:484–496. PubMed

Samuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, Kahn M, Zhang XM, Monia BP, Bhanot S, Shulman GI. Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Invest. 2007;117:739–745. doi: 10.1172/JCI30400. PubMed DOI PMC

Schmitz-Peiffer C, Browne CL, Oakes ND, Watkinson A, Chisholm DJ, Kraegen EW, Biden TJ. 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;46:169–178. doi: 10.2337/diabetes.46.2.169. PubMed DOI