Regulatory effects of arachidonate 5-lipoxygenase on hepatic microsomal TG transfer protein activity and VLDL-triglyceride and apoB secretion in obese mice

As 5-lipoxygenase (5-LO) is an emerging target in obesity and insulin resistance, we have investigated whether this arachidonate pathway is also implicated in the progression of obesity-related fatty liver disease. Our results show that 5-LO activity and 5-LO-derived product levels are significantly elevated in the liver of obese ob/ob mice with respect to wild-type controls. Treatment of ob/ob mice with a selective 5-LO inhibitor exerted a remarkable protection from hepatic steatosis as revealed by decreased oil red-O staining and reduced hepatic triglyceride (TG) concentrations. In addition, 5-LO inhibition in ob/ob mice downregulated genes involved in hepatic fatty acid uptake (i.e., L-FABP and FAT/CD36) and normalized peroxisome proliferator-activated receptor alpha (PPARα) and acyl-CoA oxidase expression, whereas the expression of lipogenic genes [i.e., fatty acid synthase (FASN) and SREBP-1c] remained unaltered. Furthermore, 5-LO inhibition restored hepatic microsomal TG transfer protein (MTP) activity in parallel with a stimulation of hepatic VLDL-TG and apoB secretion in ob/ob mice. Consistent with these findings, 5-LO products directly inhibited MTP activity and triggered cytosolic TG accumulation in CC-1 cells, a murine hepatocyte cell line. Taken together, these findings identify a novel steatogenic role for 5-LO in the liver through mechanisms involving the regulation of hepatic MTP activity and VLDL-TG and apoB secretion. As 5-lipoxygenase (5-LO) is an emerging target in obesity and insulin resistance, we have investigated whether this arachidonate pathway is also implicated in the progression of obesity-related fatty liver disease. Our results show that 5-LO activity and 5-LO-derived product levels are significantly elevated in the liver of obese ob/ob mice with respect to wild-type controls. Treatment of ob/ob mice with a selective 5-LO inhibitor exerted a remarkable protection from hepatic steatosis as revealed by decreased oil red-O staining and reduced hepatic triglyceride (TG) concentrations. In addition, 5-LO inhibition in ob/ob mice downregulated genes involved in hepatic fatty acid uptake (i.e., L-FABP and FAT/CD36) and normalized peroxisome proliferator-activated receptor alpha (PPARα) and acyl-CoA oxidase expression, whereas the expression of lipogenic genes [i.e., fatty acid synthase (FASN) and SREBP-1c] remained unaltered. Furthermore, 5-LO inhibition restored hepatic microsomal TG transfer protein (MTP) activity in parallel with a stimulation of hepatic VLDL-TG and apoB secretion in ob/ob mice. Consistent with these findings, 5-LO products directly inhibited MTP activity and triggered cytosolic TG accumulation in CC-1 cells, a murine hepatocyte cell line. Taken together, these findings identify a novel steatogenic role for 5-LO in the liver through mechanisms involving the regulation of hepatic MTP activity and VLDL-TG and apoB secretion. In the early stages of liver injury, triglycerides (TG) accumulate in the cytoplasm of hepatocytes leading to hepatic steatosis. Although generally asymptomatic, hepatic steatosis or fatty liver is no longer regarded as a neutral and innocent bystander but rather as a premorbid condition that increases the vulnerability of this organ to progress to advanced liver disease (1Angulo P. Nonalcoholic fatty liver disease.N. Engl. J. Med. 2002; 346: 1221-1231Crossref PubMed Scopus (4171) Google Scholar, 2Sanyal A.J. Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease.Nat Clin Pract Gastroenterol Hepatol. 2005; 2: 46-53Crossref PubMed Scopus (184) Google Scholar). Indeed, hepatic steatosis is frequently complicated by the presence of a prominent inflammatory component, a condition known as steatohepatitis, which may evolve in time to tissue damage and scar accumulation, progressive fibrosis, and eventually to liver cirrhosis (3Koteish A. Mae D.A. Animal models of steatohepatitis.Best Pract. Res. Clin. Gastroenterol. 2002; 16: 679-690Crossref PubMed Scopus (152) Google Scholar, 4Browning J.D. Horton J.D. Molecular mediators of hepatic steatosis and liver injury.J. Clin. Invest. 2004; 114: 147-152Crossref PubMed Scopus (1760) Google Scholar, 5den Boer M. Voshol P.J. Kuipers F. Havekes L.M. Romijn J.A. Hepatic steatosis: a mediator of the metabolic syndrome. Lessons from animal models.Arterioscler. Thromb. Vasc. Biol. 2004; 24: 644-649Crossref PubMed Scopus (224) Google Scholar). The prevalence of fatty liver disease and steatohepatitis is increasing worldwide in parallel with the rise in obesity, dyslipidemia, and insulin resistance, and they are considered the hepatic manifestations of the metabolic syndrome (1Angulo P. Nonalcoholic fatty liver disease.N. Engl. J. Med. 2002; 346: 1221-1231Crossref PubMed Scopus (4171) Google Scholar, 2Sanyal A.J. Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease.Nat Clin Pract Gastroenterol Hepatol. 2005; 2: 46-53Crossref PubMed Scopus (184) Google Scholar). The arachidonate 5-lipoxygenase (5-LO) pathway has recently been identified as an emerging target in obesity, insulin resistance, and atherosclerosis (6Zhao L. Moos M.P. Grabner R. Pedrono F. Fan J. Kaiser B. John N. Schmidt S. Spanbroek R. Lotzer K. et al.The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm.Nat. Med. 2004; 10: 966-973Crossref PubMed Scopus (304) Google Scholar, 7Kaaman M. Ryden M. Axelsson T. Nordstrom E. Sicard A. Bouloumie A. Langin D. Arner P. Dahlman I. ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance.Int. J. Obes. 2006; 30: 447-452Crossref Scopus (49) Google Scholar, 8Back M. Sultan A. Ovchinnikova O. Hansson G.K. 5-Lipoxygenase-activating protein: a potential link between innate and adaptive immunity in atherosclerosis and adipose tissue inflammation.Circ. Res. 2007; 100: 946-949Crossref PubMed Scopus (98) Google Scholar, 9Mehrabian M. Allayee H. Stockton J. Lum P.Y. Drake T.A. Castellani L.W. Suh M. Armour C. Edwards S. Lamb J. et al.Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits.Nat. Genet. 2005; 37: 1224-1233Crossref PubMed Scopus (185) Google Scholar, 10Shashkin P.N. Jain N. Miller Y.I. Rissing B.A. Huo Y. Keller S.R. Vandenhoff G.E. Nadler J.L. McIntyre T.M. Insulin and glucose play a role in foam cell formation and function.Cardiovasc. Diabetol. 2006; 5: 13Crossref PubMed Scopus (24) Google Scholar, 11Dwyer J.H. Allayee H. Dwyer K.M. Fan J. Wu H. Mar R. Lusis A.J. Mehrabian M. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis.N. Engl. J. Med. 2004; 350: 29-37Crossref PubMed Scopus (554) Google Scholar, 12Mehrabian M. Allayee H. Wong J. Shi W. Wang X.P. Shaposhnik Z. Funk C.D. Lusis A.J. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice.Circ. Res. 2002; 91: 120-126Crossref PubMed Scopus (373) Google Scholar, 13Spanbroek R. Grabner R. Lotzer K. Hildner M. Urbach A. Ruhling K. Moos M.P. Kaiser B. Cohnert T.U. Wahlers T. et expression of the 5-lipoxygenase pathway the 100: PubMed Scopus Google Scholar, H. A. M. A. Wong J. Hansson G.K. B. et of 5-lipoxygenase and in with of 2006; PubMed Scopus Google Scholar). In 5-LO protein is in the adipose tissue of obese with insulin resistance, and and gene have identified 5-LO as a gene with adipose accumulation M. Ryden M. Axelsson T. Nordstrom E. Sicard A. Bouloumie A. Langin D. Arner P. Dahlman I. ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance.Int. J. Obes. 2006; 30: 447-452Crossref Scopus (49) Google Scholar, 8Back M. Sultan A. Ovchinnikova O. Hansson G.K. 5-Lipoxygenase-activating protein: a potential link between innate and adaptive immunity in atherosclerosis and adipose tissue inflammation.Circ. Res. 2007; 100: 946-949Crossref PubMed Scopus (98) Google Scholar, 9Mehrabian M. Allayee H. Stockton J. Lum P.Y. Drake T.A. Castellani L.W. Suh M. Armour C. Edwards S. Lamb J. et al.Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits.Nat. Genet. 2005; 37: 1224-1233Crossref PubMed Scopus (185) Google Scholar). In addition, formation of 5-LO-derived products has been in and P.N. Jain N. Miller Y.I. Rissing B.A. Huo Y. Keller S.R. Vandenhoff G.E. Nadler J.L. McIntyre T.M. Insulin and glucose play a role in foam cell formation and function.Cardiovasc. Diabetol. 2006; 5: 13Crossref PubMed Scopus (24) Google Scholar). the 5-LO pathway has been as a in and an of the 5-LO gene has been identified in with of atherosclerosis J.H. Allayee H. Dwyer K.M. Fan J. Wu H. Mar R. Lusis A.J. Mehrabian M. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis.N. Engl. J. Med. 2004; 350: 29-37Crossref PubMed Scopus (554) Google Scholar, 12Mehrabian M. Allayee H. Wong J. Shi W. Wang X.P. Shaposhnik Z. Funk C.D. Lusis A.J. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice.Circ. Res. 2002; 91: 120-126Crossref PubMed Scopus (373) Google Scholar). 5-LO with inflammatory in the and to the pathogenesis of hyperlipidemia-dependent (6Zhao L. Moos M.P. Grabner R. Pedrono F. Fan J. Kaiser B. John N. Schmidt S. Spanbroek R. Lotzer K. et al.The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm.Nat. Med. 2004; 10: 966-973Crossref PubMed Scopus (304) Google Scholar, 13Spanbroek R. Grabner R. Lotzer K. Hildner M. Urbach A. Ruhling K. Moos M.P. Kaiser B. Cohnert T.U. Wahlers T. et expression of the 5-lipoxygenase pathway the 100: PubMed Scopus Google Scholar, H. A. M. A. Wong J. Hansson G.K. B. et of 5-lipoxygenase and in with of 2006; PubMed Scopus Google Scholar). the potential of the 5-LO pathway in the progression of fatty liver disease to In the we the expression, and role of 5-LO in hepatic steatosis in ob/ob an of obesity-related fatty liver disease (3Koteish A. Mae D.A. Animal models of steatohepatitis.Best Pract. Res. Clin. Gastroenterol. 2002; 16: 679-690Crossref PubMed Scopus (152) Google Scholar, models in fatty liver disease and steatohepatitis J. 2006; PubMed Scopus Google Scholar). In these we the progression of hepatic steatosis (i.e., fatty acid and fatty acid the activity of the microsomal TG transfer protein (MTP) and VLDL-TG and apoB secretion. In addition, we the of 5-LO products and mechanisms TG and in CC-1 cells, a murine hepatocyte cell line. wild-type and mice in the a mouse or a a 5-LO inhibitor inhibitor for The 5-LO inhibitor in this the a 5-LO inhibitor by with in and in R. A. A. N. E. R. M. J.L. J. protection liver and by a selective inhibitor and a 5-LO 2007; PubMed Scopus Google Scholar, L. D. O. Molecular of the 5-lipoxygenase inhibitor J. 2004; PubMed Scopus Google Scholar, J.L. for the and of 5-lipoxygenase J. PubMed Scopus Google Scholar). the by to in the of the and the 5-LO inhibition in wild-type mice R. A. A. N. E. R. M. J.L. J. protection liver and by a selective inhibitor and a 5-LO 2007; PubMed Scopus Google and in ob/ob mice the of the mice with and by The liver in and in for The liver tissue in for and or in for oil red-O animal in with the of the and of the and the the of Hepatic steatosis by oil red-O staining in in for and with oil red-O in for and with with with acid and with a a of and of steatosis as oil red-O by a of The in VLDL-TG as F. S. to and secretion in an for a of and of to Res. 37: PubMed Google Scholar, M. R. Boer T. Romijn J.A. Kuipers F. Hepatic in ob/ob mice is not by but is to the of PubMed Scopus Google Scholar, R. Kuipers F. hepatic in mice the liver receptor Res. 2007; PubMed Scopus Google with and ob/ob mice mouse or a the 5-LO inhibitor for the of mice an of of as a of in the by and and the of the a by for of VLDL-TG levels with the and a of in a The VLDL-TG from the of TG the time and as in as F. S. to and secretion in an for a of and of to Res. 37: PubMed Google Scholar, M. R. Boer T. Romijn J.A. Kuipers F. Hepatic in ob/ob mice is not by but is to the of PubMed Scopus Google Scholar, R. Kuipers F. hepatic in mice the liver receptor Res. 2007; PubMed Scopus Google with of in for and through for in and and with an for with a and an by the by with a for in an a The and of apoB of and fatty as as and and by insulin levels an Insulin The hepatic of and TG by with tissue in and an the of and the for for the a and in of TG in from cell and a of whereas and for and in and an for of and the for for TG with a 5-LO activity in liver from wild-type and ob/ob mice. of with of arachidonic acid and for in a the of the for and the of 5-LO products by E. J. A. M. N. M. A. R. W. et of 5-lipoxygenase cell and in for liver J. PubMed Scopus Google Scholar, E. J. A. M. A. R. J. of protein liver role of Biol. 2005; PubMed Scopus Google Scholar). 5-LO activity as the of and time and as The accumulation of and in the liver of wild-type mice and ob/ob mice in of that with a in of and with to E. J. A. M. N. M. A. R. W. et of 5-lipoxygenase cell and in for liver J. PubMed Scopus Google Scholar, E. J. A. M. A. R. J. of protein liver role of Biol. 2005; PubMed Scopus Google Scholar). CC-1 cells, an hepatocyte cell M. J. T. by in a liver cell PubMed Scopus Google from the of CC-1 in a in with and TG levels and gene expression the a of and the with with the to or increasing and of and and cell as in the and gene expression from cell as In insulin to the or the with of receptor by or of receptor for by the of or MTP activity by a and in which with and of tissue in of and protein the the MTP in in of and and of liver for and in a and of to of The of by to MTP activity with MTP activity as the of of MTP activity in from cell CC-1 a of with with and to and or and with by with K. for with with and a In these of protein with an time of whether and directly MTP from CC-1 a of of protein with of and and and and in for MTP activity for an time of of from liver tissue and and the in a and a in a from of the and and from products to 5-LO MTP and and fatty acid synthase and liver fatty protein and fatty acid and peroxisome proliferator-activated receptor and and acyl-CoA oxidase and and as an in an results with the of gene expression the The of target normalized to and to a by the in the of the results the and as and considered The of and the and products of the arachidonate 5-LO significantly in of liver from ob/ob mice with from wild-type mice liver tissue from ob/ob mice and with arachidonic acid significantly of 5-LO products liver tissue from wild-type 5-LO levels in the liver of ob/ob mice In the ob/ob mouse 5-LO activity and and levels reduced by a selective 5-LO inhibitor the of hepatic 5-LO activity to the of hepatic steatosis in ob/ob mice. that and liver and and insulin significantly in ob/ob mice. In to obesity, and ob/ob mice and and remarkable hepatic steatosis as revealed by of oil liver and by the presence of hepatic TG The of the selective 5-LO to these mice significantly hepatic steatosis as the of the with oil red-O reduced in these obese mice associated with a of hepatic TG decreased and TG and fatty acid levels in ob/ob mice 5-LO inhibition Hepatic levels and and insulin and and by 5-LO in in wild-type mice with the 5-LO inhibitor not and liver and in wild-type mice mice and ob/ob mice the 5-LO inhibitor 5-LO 5-LO to TG fatty insulin not are as in a not are as the mechanisms the associated with 5-LO we genes hepatic fatty acid and fatty acid in ob/ob mice. levels of genes involved in hepatic [i.e., fatty acid synthase fatty acid uptake [i.e., fatty acid and of fatty [i.e., and the acyl-CoA oxidase in of ob/ob mice. In these obese 5-LO inhibition significantly downregulated the expression of genes associated with fatty acid uptake [i.e., liver fatty protein and and normalized the expression of and the expression of genes involved in as and remained in wild-type mice with the 5-LO inhibitor of role in the of in the of TG from we the of 5-LO inhibition MTP As in with wild-type the activity of this microsomal transfer protein significantly decreased in from ob/ob mice and restored the inhibition of the 5-LO MTP expression not in ob/ob mice and not by 5-LO inhibition in the of 5-LO inhibition VLDL-TG by ob/ob and mice with Consistent with M. R. Boer T. Romijn J.A. Kuipers F. Hepatic in ob/ob mice is not by but is to the of PubMed Scopus Google hepatic VLDL-TG remained in ob/ob mice 5-LO inhibition a in hepatic VLDL-TG in ob/ob mice In parallel with findings in MTP the apoB of the significantly reduced in ob/ob mice and restored by inhibition of the 5-LO pathway that that MTP activity are known to we the of 5-LO products (i.e., and MTP activity in CC-1 cells, an hepatocyte cell line. Consistent with findings 5-LO inhibition in reduced MTP activity in a in CC-1 hepatocyte MTP the whether 5-LO products directly MTP from CC-1 with of and and MTP activity in the As in MTP activity decreased in the presence of of and findings are with the that a selective receptor a selective receptor to the of and hepatocytes not that are not by to cell The of CC-1 with and the expression of genes and are in Consistent with in findings, expression of MTP in CC-1 by 5-LO and and show and L-FABP expression by of CC-1 with and not in in and expression, that the in ob/ob mice 5-LO inhibition in to the in is a of levels and liver liver disease and fatty acid J. 2006; PubMed Scopus Google Scholar). The steatogenic of 5-LO products hepatocytes by and TG levels in CC-1 with increasing of and and As in a in TG in parallel with a in TG concentrations. the an accumulation of TG by a of and expression in the presence of an of findings, with The steatogenic by 5-LO products by the of insulin to the cell not have in to in inflammatory the 5-LO pathway is also associated with metabolic disease obesity, and insulin (6Zhao L. Moos M.P. Grabner R. Pedrono F. Fan J. Kaiser B. John N. Schmidt S. Spanbroek R. Lotzer K. et al.The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm.Nat. Med. 2004; 10: 966-973Crossref PubMed Scopus (304) Google Scholar, 7Kaaman M. Ryden M. Axelsson T. Nordstrom E. Sicard A. Bouloumie A. Langin D. Arner P. Dahlman I. ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance.Int. J. Obes. 2006; 30: 447-452Crossref Scopus (49) Google Scholar, 8Back M. Sultan A. Ovchinnikova O. Hansson G.K. 5-Lipoxygenase-activating protein: a potential link between innate and adaptive immunity in atherosclerosis and adipose tissue inflammation.Circ. Res. 2007; 100: 946-949Crossref PubMed Scopus (98) Google Scholar, 9Mehrabian M. Allayee H. Stockton J. Lum P.Y. Drake T.A. Castellani L.W. Suh M. Armour C. Edwards S. Lamb J. et al.Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits.Nat. Genet. 2005; 37: 1224-1233Crossref PubMed Scopus (185) Google Scholar, 10Shashkin P.N. Jain N. Miller Y.I. Rissing B.A. Huo Y. Keller S.R. Vandenhoff G.E. Nadler J.L. McIntyre T.M. Insulin and glucose play a role in foam cell formation and function.Cardiovasc. Diabetol. 2006; 5: 13Crossref PubMed Scopus (24) Google Scholar, 11Dwyer J.H. Allayee H. Dwyer K.M. Fan J. Wu H. Mar R. Lusis A.J. Mehrabian M. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis.N. Engl. J. Med. 2004; 350: 29-37Crossref PubMed Scopus (554) Google Scholar, 12Mehrabian M. Allayee H. Wong J. Shi W. Wang X.P. Shaposhnik Z. Funk C.D. Lusis A.J. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice.Circ. Res. 2002; 91: 120-126Crossref PubMed Scopus (373) Google Scholar, 13Spanbroek R. Grabner R. Lotzer K. Hildner M. Urbach A. Ruhling K. Moos M.P. Kaiser B. Cohnert T.U. Wahlers T. et expression of the 5-lipoxygenase pathway the 100: PubMed Scopus Google Scholar, H. A. M. A. Wong J. Hansson G.K. B. et of 5-lipoxygenase and in with of 2006; PubMed Scopus Google Scholar). In the we for the time to that the 5-LO pathway is also implicated in the pathogenesis of fatty liver disease. In findings hepatic 5-LO activity and 5-LO product formation and in ob/ob a of obesity-related hepatic steatosis (3Koteish A. Mae D.A. Animal models of steatohepatitis.Best Pract. Res. Clin. Gastroenterol. 2002; 16: 679-690Crossref PubMed Scopus (152) Google Scholar, models in fatty liver disease and steatohepatitis J. 2006; PubMed Scopus Google Scholar). Our findings also a role for 5-LO products in hepatic steatosis by mechanisms a in hepatic MTP activity and VLDL-TG and apoB secretion and an of genes involved in the uptake of fatty (i.e., a microsomal protein in the is the for the of in hepatic Shi J. P. triglyceride transfer protein and role in Res. PubMed Scopus Google Scholar, H. Y. M. D.A. that microsomal triglyceride transfer protein is in the of in hepatic Res. PubMed Google Scholar, P. A. A. B. D. of microsomal triglyceride transfer protein: for steatosis in PubMed Scopus Google Scholar, E. S. E. D. C. C. I. E. M. of microsomal triglyceride transfer protein in the role in the of Biol. 2002; PubMed Scopus Google Scholar). The role of MTP is to the transfer of to the which is to by the of Shi J. 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