Palmitate-induced downregulation of lipocalin prostaglandin D(2) synthase accompanies hepatic lipid accumulation in HepG2 cells.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with multiple metabolic dysfunctions and poses a significant global health challenge. Our prior in vivo studies demonstrated that the absence of lipocalin prostaglandin D2 synthase (L-PGDS) leads to the development of fatty liver disease, and L-PGDS expression significantly decreased when C57BL/6 mice were kept on a high-fat diet. Briefly, L-PGDS belongs to the arachidonic acid pathway and enzymatically isomerizes prostaglandin H2 to prostaglandin D2, which imparts pharmacological effects via two receptors called DP1 and DP2. L-PGDS is an essential key player in fatty liver disease, but its mechanistic regulation still remains unknown. Therefore, we aimed to study the mechanistic regulation of L-PGDS using a palmitate-induced cellular MASLD model. We successfully recapitulated the MASLD phenotype in HepG2 cells with palmitate treatment. Our results showed significant lipid accumulation and increased lipidassociated protein and gene expression, along with palmitate concentration-dependent L-PGDS downregulation. To study the L-PGDS downregulation, we employed MG132, chloroquine, and cycloheximide to assess proteasomal degradation, autophagy, and translational activity, respectively. Our gene and protein expression data suggested the possible reason for L-PGDS downregulation via inhibiting transcription and subsequently translation. Additionally, our autophagy results also showed a role in LPGDS downregulation. In summary, it can be concluded that palmitate treatment downregulated L-PGDS, possibly involving transcription-translation and/or autophagy pathways. However, further studies are needed to delineate the precise molecular mechanism and apply this knowledge to MASLD pathogenesis and treatment.