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Hepatic and plasma sex differences in saturated and monounsaturated fatty acids are associated with differences in expression of elongase 6, but not stearoyl-CoA desaturase in Sprague-Dawley rats.

ABSTRACT: Monounsaturated fatty acids (MUFA) have been viewed as either beneficial or neutral with respect to health; however, recent evidence suggests that MUFA may be associated with obesity and cardiovascular disease. Sex differences in MUFA composition have been reported in both rats and humans, but the basis for this sexual dimorphism is unknown. In the current study, enzymes involved in MUFA biosynthesis are examined in rat and cell culture models. Male and female rats were maintained on an AIN-93G diet prior to killing at 14 weeks of age after an overnight fast. Concentrations of 16:0 (2,757 ± 616 vs. 3,515 ± 196 ?g fatty acid/g liver in males), 18:1n-7 (293 ± 66 vs. 527 ± 49 ?g/g) and 18:1n-9 (390 ± 80 vs. 546 ± 47 ?g/g) were lower, and concentrations of 18:0 (5,943 ± 1,429 vs. 3,987 ± 325 ?g/g) were higher in phospholipids in livers from female rats compared with males. Hepatic elongase 6 mRNA and protein were 5.9- and 2.0-fold higher, respectively, in females compared with males. Stearoyl-CoA desaturase expression did not differ. Specific hormonal effects were examined in HepG2 cells cultured with varying concentrations of 17?-estradiol, progesterone and testosterone (0, 10, 30 and 100 nM) for 72 h. Progesterone and 17?-estradiol treatments increased, while testosterone decreased, elongase 6 protein. Sex differences in MUFA composition were associated with increased expression of hepatic elongase 6 in females relative to male rats, which appears to be mediated by sex hormones based on observations of hormonal treatments of HepG2 cells.

SUBMITTER: Marks KA

PROVIDER: S-EPMC3639325 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Hepatic and plasma sex differences in saturated and monounsaturated fatty acids are associated with differences in expression of elongase 6, but not stearoyl-CoA desaturase in Sprague-Dawley rats.

Marks Kristin A KA Kitson Alex P AP Stark Ken D KD

Genes & nutrition 20121122 3

Monounsaturated fatty acids (MUFA) have been viewed as either beneficial or neutral with respect to health; however, recent evidence suggests that MUFA may be associated with obesity and cardiovascular disease. Sex differences in MUFA composition have been reported in both rats and humans, but the basis for this sexual dimorphism is unknown. In the current study, enzymes involved in MUFA biosynthesis are examined in rat and cell culture models. Male and female rats were maintained on an AIN-93G ...[more]

PMID: 23180365

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Project description:Background & aimsAramchol is a fatty acid-bile acid conjugate that reduces liver fat content and is being evaluated in a phase III clinical trial for non-alcoholic steatohepatitis (NASH). Aramchol attenuates NASH in mouse models and decreases steatosis by downregulating the fatty acid synthetic enzyme stearoyl CoA desaturase 1 (SCD1) in hepatocytes. Although hepatic stellate cells (HSCs) also store lipids as retinyl esters, the impact of Aramchol in this cell type is unknown.MethodsWe investigated the effects of Aramchol on a human HSC line (LX-2), primary human HSCs (phHSCs), and primary human hepatocytes (phHeps).ResultsIn LX-2 and phHSCs, 10 μM Aramchol significantly reduced SCD1 mRNA while inducing PPARG (PPARγ) mRNA, with parallel changes in the 2 proteins; ACTA2, COL1A1, β-PDGFR (bPDGFR) mRNAs were also significantly reduced in LX-2. Secretion of collagen 1 (Col1α1) was inhibited by 10 μM Aramchol. SCD1 knockdown in LX-2 cells phenocopied the effect of Aramchol by reducing fibrogenesis, and addition of Aramchol to these cells did not rescue fibrogenic gene expression. Conversely, in LX-2 overexpressing SCD1, Aramchol no longer suppressed fibrogenic gene expression. The drug also induced genes in LX-2 that promote cholesterol efflux and inhibited ACAT2, which catalyses cholesterol synthesis. In phHeps, Aramchol also reduced SCD1 and increased PPARG mRNA expression.ConclusionsAramchol downregulates SCD1 and elevates PPARG in HSCs, reducing COL1A1 and ACTA2 mRNAs and COL1A1 secretion. These data suggest a direct inhibitory effect of Aramchol in HSCs through SCD1 inhibition, as part of a broader impact on both fibrogenic genes as well as mediators of cholesterol homeostasis. These findings illustrate novel mechanisms of Aramchol activity, including potential antifibrotic activity in patients with NASH and fibrosis.Lay summaryIn this study, we have explored the potential activity of Aramchol, a drug currently in clinical trials for fatty liver disease, in blocking fibrosis, or scarring, by hepatic stellate cells, the principal collagen-producing (i.e. fibrogenic) cell type in liver injury. In both isolated human hepatic stellate cells and in a human hepatic stellate cell line, the drug suppresses the key fat-producing enzyme, stearoyl CoA desaturase 1 (SCD1), which leads to reduced expression of genes and proteins associated with hepatic fibrosis, while inducing the protective gene, PPARγ. The drug loses activity when SCD1 is already reduced by gene knockdown, reinforcing the idea that inhibition of SCD1 is a main mode of activity for Aramchol. These findings strengthen the rationale for testing Aramchol in patients with NASH.

Dataset Information

Hepatic and plasma sex differences in saturated and monounsaturated fatty acids are associated with differences in expression of elongase 6, but not stearoyl-CoA desaturase in Sprague-Dawley rats.

Publications

Hepatic and plasma sex differences in saturated and monounsaturated fatty acids are associated with differences in expression of elongase 6, but not stearoyl-CoA desaturase in Sprague-Dawley rats.

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