High-altitude hypoxia remodels lipid metabolism in renal tubular epithelial cells by inhibiting the expression of HNF4α.

A deficiency of fatty acid oxidation (FAO) is the key hallmark in renal tubular epithelial cells (TECs) under high-altitude hypoxia (HH), reflecting their physiological reliance on FAO as a major energy source. The resulting lipid accumulation is likely to promote lipotoxicity-induced pathological injury in renal tissue. However, the molecular mechanisms underlying HH-induced renal lipotoxic injury remain poorly understood. This study identifies hepatocyte nuclear factor 4α (HNF4α) as a key regulator of lipid metabolism. HNF4α expression in kidney tissues was significantly downregulated after HH exposure. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis revealed that HNF4α directly binds to and regulates the transcription of the Acyl-CoA Oxidase 1 (ACOX1), a key gene involved in FAO, in the kidney of hypoxia- exposed rats. Further functional studies indicated that lentivirus-mediated overexpression of HNF4α significantly alleviated hypoxia-induced lipid accumulation and the decrease in adenosine triphosphate (ATP) production, while effectively inhibiting cell apoptosis. In contrast, knockdown of HNF4α markedly aggravated cellular lipotoxicity, as evidenced by increased intracellular lipid accumulation, reduced ATP levels, and enhanced apoptosis. Mechanistically, HNF4α directly activates ACOX1 transcription and modulates Carnitine Palmitoyltransferase1A (CPT1A) expression, thereby enhancing FAO capacity. This leads to reduced reactive oxygen species (ROS) accumulation, improved mitochondrial membrane potential, and promoted ATP synthesis, ultimately mitigating hypoxia-related cellular injury. Overall, our findings uncover a previously unrecognized role for HNF4α in maintaining lipid homeostasis in TECs under hypoxic conditions and provide novel mechanism and target for HH-associated kidney injury.