ARS | Publication request: The Heparan and Heparin Metabolism Pathway is Involved in Regulation of Fatty Acid Composition

Submitted to: International Journal of Biological Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 16, 2011
Publication Date: May 21, 2011
Citation: Jiang, Z., Michal, J., Wu, X., Pan, Z., MacNeil, M.D. 2011. The Heparan and Heparin Metabolism Pathway is Involved in Regulation of Fatty Acid Composition. International Journal of Biological Sciences. 7(5):659-663.

Interpretive Summary: Bipolar disorder, characterized by vulnerability to episodic depression and mania and spontaneous cycling is a genetically based neuropsychiatric disorder with high heritability. Genes associated with bipolar disorder code for enzymes and proteins are involved in heparan sulfate and heparin metabolism. Many bipolar patients are obese, suggesting that mutations in genes important to the disorder in humans may affect adiposity. In the present study, we examined the dopamine signaling pathway associated with bipolar disorder for effects on lipid metabolism. Wagyu x Limousin F2 calves were genotyped for six mutations and resulting genotypes were tested for association with carcass, eating quality and fatty acid composition traits. Results show enzymes are involved in heparan sulfate and heparin metabolism indeed do affect fatty acid composition of skeletal muscle. How these enzymes modify structures of heparan sulfate and heparin in cells and then lead to different fatty acid profiles in muscle cells warrants further investigation.

Technical Abstract: Six genes involved in the heparan sulfate and heparin metabolism pathway, DSEL (dermatan sulfate epimerase-like), EXTL1 (exostoses (multiple)-like 1), HS6ST1 (heparan sulfate 6-O-sulfotransferase 1), HS6ST3 (heparan sulfate 6-O-sulfotransferase 3), NDST3 (N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 3), and SULT1A1 (sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1), were investigated for their associations with muscle lipid compositions using cattle as a model organism. Nineteen single nucleotide polymorphisms (SNPs)/multiple nucleotide length polymorphisms (MNLPs) were identified in five of these six genes. Six of these mutations were then genotyped on 246 Wagyu x Limousin F2 animals, which were measured for 5 carcass, 6 eating quality and 8 fatty acid composition traits. Association analysis revealed that DSEL, EXTL1 and HS6ST1 significantly affected two stearoyl-CoA desaturase activity indices, the amount of conjugated linoleic acid (CLA) and the relative amount of saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) in skeletal muscle (P<0.05). In particular, HS6ST1 joined our previously reported SCD1 and UQCRC1 genes to form a three gene network for one of the stearoyl-CoA desaturase activity indices. As several genome-wide association studies (GWAS) conducted in humans reported the heparan sulfate and heparin pathway enriched for bipolar disorder, our present study might provide novel insights into understanding of its pathobiology.