Low temperature rather than hypoxia drives cholesterol synthesis and oxygen consumption in plateau zokors

Subterranean burrows of plateau zokors (Eospalax baileyi) on the Qinghai-Tibet Plateau become significantly colder and more hypoxic with increasing altitude. Because cholesterol biosynthesis is highly oxygen-intensive, it is typically inhibited by hypoxia. Here, our findings revealed that with increasing altitude, the expression and activation of SREBP2, alongside FDFT1 and SQLE expression, were significantly upregulated in the liver. Furthermore, the incomplete degradation of SQLE produced two distinct isoforms. High-altitude zokors showed an increase in the active trunSQLE-1 and a concomitant decrease in the inactive trunSQLE-2, completely opposite to low-altitude zokors. Additionally, blood cholesterol and oxygen consumption increased significantly, with no significant difference in arterial oxygen saturation. Notably, body weight changes of plateau zokors conformed to Bergmann's rule. These results suggested that the elevated cholesterol synthesis was not hypoxia-induced. Therefore, the increase in cholesterol synthesis in plateau zokors likely results from adaptation to the cold and humid underground burrow habitat.