Hexose-6-phosphate dehydrogenase deficiency disrupts hepatic fatty acid homeostasis and induces triglyceride accumulation

Hexose-6-phosphate dehydrogenase (H6PD) is crucial in an enzymatic process known as the pentose phosphate pathway within the endoplasmic reticulum of cells. This pathway helps maintain appropriate levels of NADPH, a vital coenzyme involved in various cellular processes. Despite H6PD's significance, its precise function remains somewhat elusive.

Notably, H6PD is expressed abundantly in the liver, making it an intriguing subject of study for its potential impact on lipid metabolism within this organ. To investigate this hypothesis, a team of researchers developed an H6PD knockout mouse strain. By employing advanced lipidomic and proteomic techniques, they discovered that H6PD knockout mice exhibited elevated levels of triglycerides, particularly unsaturated long-chain triglycerides, in their liver tissue.

Confirmed through staining techniques, these findings indicated intracellular lipid accumulation in the H6PD-deficient mice. Further analysis of the proteomics data unveiled an upregulation of several pathways involved in fatty acid metabolism. To validate these findings, researchers also generated an H6PD knockout AML12 cell line via CRISPR/Cas9 technology.

This cell line displayed intracellular lipid accumulation, reduced mitochondrial beta-oxidation, and heightened sensitivity to lipotoxicity. Despite this, fatty acids continued to serve as the primary fuel for mitochondrial respiration in these affected cells. In conclusion, these comprehensive studies underscore H6PD's previously uncharacterized role in hepatic lipid metabolism, suggesting a potential interplay between NADPH availability in the endoplasmic reticulum and the regulation of fatty acid homeostasis.