Differential gene expression in liver and small intestine from lactating rats compared to age-matched virgin controls detects increased mRNA of cholesterol biosynthetic genes

Abstract

BackgroundLactation increases energy demands four- to five-fold, leading to a two- to three-fold increase in food consumption, requiring a proportional adjustment in the ability of the lactating dam to absorb nutrients and to synthesize critical biomolecules, such as cholesterol, to meet the dietary needs of both the offspring and the dam. The size and hydrophobicity of the bile acid pool increases during lactation, implying an increased absorption and disposition of lipids, sterols, nutrients, and xenobiotics. In order to investigate changes at the transcriptomics level, we utilized an exon array and calculated expression levels to investigate changes in gene expression in the liver, duodenum, jejunum, and ileum of lactating dams when compared against age-matched virgin controls.ResultsA two-way mixed models ANOVA was applied to detect differentially expressed genes. Significance calls were defined as a p < 0.05 for the overall physiologic state effect (lactation vs. control), and a within tissue pairwise comparison of p < 0.01. The proportion of false positives, an estimate of the ratio of false positives in the list of differentially expressed genes, was calculated for each tissue. The number of differentially expressed genes was 420 in the liver, 337 in the duodenum, 402 in the jejunum, and 523 in the ileum. The list of differentially expressed genes was in turn analyzed by Ingenuity Pathways Analysis (IPA) to detect biological pathways that were overrepresented. In all tissues, sterol regulatory element binding protein (Srebp)-regulated genes involved in cholesterol synthesis showed increased mRNA expression, with the fewest changes detected in the jejunum. We detected increased Scap mRNA in the liver only, suggesting an explanation for the difference in response to lactation between the liver and small intestine. Expression of Cyp7a1, which catalyzes the rate limiting step in the bile acid biosynthetic pathway, was also significantly increased in liver. In addition, decreased levels of mRNA associated with T-cell signaling were found in the jejunum and ileum. Several members of the Solute Carrier (SLC) and Adenosine Triphosphate Binding Cassette (ABC) superfamilies of membrane transporters were found to be differentially expressed; these genes may play a role in differences in nutrient and xenobiotic absorption and disposition. mRNA expression of SLC39a4_predicted, a zinc transporter, was increased in all tissues, suggesting that it is involved in increased zinc uptake during lactation. Microarray data are available through GEO under GSE19175.ConclusionsWe detected differential expression of mRNA from several pathways in lactating dams, including upregulation of the cholesterol biosynthetic pathway in liver and intestine, consistent with Srebp activation. Differential T-Cell signaling in the two most distal regions of the small intestine (ileum and jejunum) was also noted, as well as differential expression of transporters that likely play a key role in nutrient uptake.

Redistribution of tissue zinc pools during lactation and dyshomeostasis during marginal zinc deficiency in mice

“…Previous reports speculated that increased SLC39A4 (ZIP4) expression in the liver increases liver Zn concentration during lactation [36]; however, we found that liver Zn concentration is actually lower during lactation, which we speculate reflects normal metabolic adaptations that occur. For example, lactation decreases hepatic lipogenesis [21], suggesting a shift in Zn-dependent enzyme activities related to hepatic lipid metabolism to support milk production [37].…”

Hepatic bile acids and bile acid-related gene expression in pregnant and lactating rats

“…Lactating rats have a 2 to 3-fold increase in food consumption to ensure lactating dams absorb nutrients and synthesize critical molecules including bile acids to meet the dietary needs of the offspring and the dam (Vernon et al, 2002). The size and hydrophobicity of the bile acid pool increase during lactation, implying an increased absorption and disposition of lipid, sterols, nutrients, and xenobiotics (Athippozhy et al, 2011). In essence, rats (Wooton-Kee, Cohen & Vore, 2008) are different from mice (Aleksunes et al, 2012) in bile acid homeostasis during lactation.…”

“…Significant physiological changes occur during pregnancy and lactation to support the nutritional demands of the developing fetus and lactating pups (Carlin & Alfirevic, 2008; Athippozhy et al, 2011). Bile acids and cholesterol metabolism are important changes during pregnancy and lactation to support and to protect offspring development (Wooton-Kee, Cohen & Vore, 2008; Athippozhy et al, 2011; Abu-Hayyeh, Papacleovoulou & Williamson, 2013).…”

“…Bile acids and cholesterol metabolism are important changes during pregnancy and lactation to support and to protect offspring development (Wooton-Kee, Cohen & Vore, 2008; Athippozhy et al, 2011; Abu-Hayyeh, Papacleovoulou & Williamson, 2013). Such physiological changes would also affect hepatic drug processing genes of phase-1, phase-2 metabolism and transporters (Aleksunes et al, 2012; Shuster et al, 2013).…”

Proper antiviral therapy for hepatitis B virus–associated acute-on-chronic liver failure

“…Cleavage of internal thiol ester results in the formation of nascent α 2 M with reactive glutamyl and cysteinyl residues in each of its subunit. Glutamyl residue may form a covalent linkage with lysine of proteinase and the cysteinyl residue may bind cytokines (Athippozhy et al, 2011) or A chain of the plant toxin, ricin (Pop et al, 2005). The Receptor‐Binding Site : It is a 138 amino acid sequence present at the C‐terminal of each subunit of α 2 M. The receptor‐binding site is exposed only after conformational change in the structure of α 2 M, so that only the α 2 M–proteinase complex is cleared, and not the native α 2 M. The binding site is recognized by the 600 kDa α 2 M receptor which is a cell surface glycoprotein (Strickland et al, 1990; Wyatt and Wilson, 2012), a member of low‐density lipoprotein (LDL) superfamily (Pires et al, 2012; Wild et al, 2012).…”