Transcriptional downregulation of sterol metabolism genes in murine liver exposed to acute hypobaric hypoxia.

ABSTRACT

Ascent to high-altitude results in decreased inspired partial pressure of oxygen because of a decrease in barometric pressure. Altitude acclimatization requires physiological and metabolic changes to improve tolerance to altitude hypoxia. Cellular response to hypoxia results into changes in the profile of gene expression and the present study explored the same in murine model. Liver being the largest metabolic organ, the molecular details of acute hypobaric hypoxia (AHH) induced transcriptional changes in the tissue were investigated. Swiss albino mice were exposed to hypobaric hypoxia ( approximately 426mmHg) in a decompression chamber and cDNA microarray was used to study the transcriptional profile in liver. Notably, by the tenth hour several of the genes involved in sterol metabolism such as SREBF1, INSIG1, HMGCS1, FDFT1, SQLE, and HSD3B4 were downregulated more than 2-fold suggesting that AHH suppresses sterol biosynthesis in the liver. Real-time PCR helped validate the downregulation of SREBF1, HMGCS1, FDFT1, and HSD3B4 genes. However, no significant change was observed in the serum cholesterol levels throughout the AHH exposure. The findings are indicative of transcriptional downregulation of SREBP target genes as a part of acclimatization response to hypoxia. The study highlights the significance of SREBP in the regulation of sterol metabolism under the acute hypoxic response.