Peroxisome-Deficiency and HIF-2α Signaling Are Negative Regulators of KHK Expression

Ketohexokinase (KHK) is the first and rate-limiting enzyme of fructose metabolism. Expression of the alternatively spliced isoforms, KHK-A and KHK-C, is tissue-specific. KHK-C is predominantly expressed in liver, kidney and intestine and responsible for the fructose-catabolizing function. KHK isoform choice is linked to the development of various disorders such as diabetes, liver disease and cancer, but little is known about the regulation of total KHK expression. The Kovacs group investigated how hypoxic signaling influences hepatic fructose metabolism via stabilization of hypoxia-inducible factors (HIF-1α and HIF-2α). Hepatic KHK expression is suppressed byHIF-2α but not by HIF-1α signaling on mRNA and protein levels. HIF-2α activation also augments peroxisome degradation and decreases the number of peroxisomes.

Further, they demonstrated that fructose metabolism is negatively regulated by peroxisome-deficiency. Interestingly, both HIF-2α and peroxisome-deficiency result in downregulation of Khk independent of splicing. Hence, their study offers new and unexpected insights into the general regulation of KHK, and therefore fructolysis. They revealed a novel regulatory function of HIF-2α, suggesting that HIF-1α and HIF-2α have tissue-specific opposing roles in the regulation of Khk expression, isoform choice and fructolysis. In addition, they discovered a previously unknown function of peroxisomes in the regulation of fructose metabolism.

Link to the paper in external page “Frontiers in Cell and Developmental Biology”.