The ribonucleoprotein hnRNP K promotes hepatic steatosis by suppressing the nuclear hormone receptor PPARα.

Ectopic triglyceride accumulation resulting from impaired fatty acid β-oxidation (FAO) plays a crucial role in metabolic dysfunction-associated steatotic liver disease. The PPARα activation can promote FAO, thus reducing hepatic lipid levels. HnRNP K is known to act as an enhancer or repressor to regulate gene transcription, yet the relevance of hnRNP K to lipid metabolism remains elusive. In this study, hnRNP K is upregulated in diet-induced obesity mice livers and mouse primary hepatocytes stimulated with fatty acids. Functionally, hnRNP K overexpression promotes lipid deposition induced by fatty acids at the cellular level and also drives the development of diet-induced hepatosteatosis in mice. Conversely, knockdown of hnRNP K confers protection against hepatic lipid deposition. Mechanistically, Ppara is identified as a candidate target through integrating CUT&Tag-Seq and RNA-Seq. Moreover, hnRNP K represses Ppara expression by binding to its promoter, thus reducing FAO enzymes. Etomoxir, an FAO inhibitor, counteracted the alleviation of lipid accumulation induced by hnRNP K knockdown. In summary, this study demonstrates hnRNP K has a crucial role in modulating the function of PPARα and hepatic lipid metabolism.