Distinct Alteration of Gene Expression Programs in the Small Intestine of Male and Female Mice in Response to Ablation of Intestinal Fabp Genes

Abstract

Fatty acid-binding proteins (Fabps) make up a family of widely distributed cytoplasmic lipid-binding proteins. The small intestine contains three predominant Fabp species, Fabp1, Fabp2, and Fabp6. Our previous studies showed that Fabp2 and Fabp6 gene-disrupted mice exhibited sexually dimorphic phenotypes. In this study, we carried out a systematic comparative analysis of the small intestinal transcriptomes of 10 week-old wild-type (WT) and Fabp gene-disrupted male and female mice. We found that the small intestinal transcriptome of male and female mice showed key differences in the gene expression profiles that affect major biological processes. The deletion of specific Fabp genes induced unique and sex-specific changes in the gene expression program, although some differentially expressed genes in certain genotypes were common to both sexes. Functional annotation and interaction network analyses revealed that the number and type of affected pathways, as well as the sets of interacting nodes in each of the Fabp genotypes, are partitioned by sex. To our knowledge, this is the first time that sex differences were identified and categorized at the transcriptome level in mice lacking different intestinal Fabps. The distinctive transcriptome profiles of WT male and female small intestine may predetermine the nature of transcriptional reprogramming that manifests as sexually dimorphic responses to the ablation of intestinal Fabp genes.

Essential Fatty Acid Deficiency in Cystic Fibrosis Disease Progression: Role of Genotype and Sex

“…In the liver they are stored or released as required [ 11 ]. In the intestine, fatty acids are taken up by FATP4 [ 12 ] and intracellularly by FABP 1/2/6 in the small intestine [ 13 ], where they are activated by acyl-CoA, then shuttled via acyl-CoA binding protein to mitochondria or peroxisomes for β-oxidation, or to the endoplasmic reticulum for esterification. Some free fatty acids may bind to transcription factors that regulate gene expression or may be converted into signalling molecules (eicosanoids).…”

Exfoliated epithelial cell transcriptome reflects both small and large intestinal cell signatures in piglets

“…FABP2 (I-FABP) expression is highest in the distal half of small intestine. FABP2 shows a preference for transporting saturated long-chain fatty acids, but targeted gene deletion of the FABP2 gene in rodents results in sexually dimorphic metabolic disturbances and changes in gene expression, supporting broader roles for this protein (30). During tissue injury, FABP-2 is released and can be measured in the serum and urine and has been proposed as a luminally expressed biomarker of intestinal injury (31,32).…”

Importance of fatty acid binding proteins in cellular function and organismal metabolism

“…sex, genetic background, nutrient status) is an important modifier of the phenotypic outcomes of Fabp gene inactivation 14,15,37,85,86 . In regards to phenotypic differences observed between sexes and in mice with different genetic backgrounds, it is now known that the gene expression programs of males and females, or that of different mouse strains, are not identical 18,87,88 . Alternative methods for inhibiting gene expression in wild‐type organisms are now available.…”

“…Mice lacking Fabp5 (legacy name: E‐Fabp) exhibit a slight diminution of basal transepidermal water loss, 83 but became resistant to experimental autoimmune encephalomyelitis (EAE) induction, a mouse model of inflammatory demyelinating disease 84 . It also became apparent that sex is an important modifying parameter since males and females do not always show the same outcomes from Fabp deficiency 15,18,36,85 . Furthermore, Fabp1‐deficient mice of different genetic backgrounds do not show identical phenotypes, indicating that this specific Fabp type is not serving one dominant functional role 37 .…”

“…Strikingly however, genetic ablation of specific Fabp genes do not seem to cause lethality nor detrimental phenotypes, although their absence has been seen to cause some metabolic perturbations that are evident at the organismal level 14–17 . In some cases, loss of Fabps modify gene expression programs in a sex‐dependent manner 18 . Another notable feature of Fabps is the correlation of their increased abundance in individuals with particular diseases or pathological conditions.…”