The liver is a key metabolic organ with functions in glucose and lipid metabolism, and whose dysfunction and inflammation are intimately linked to many metabolic disorders such as type 2 diabetes, nonalcoholic fatty liver disease, and hepatocellular carcinoma. The immunoproteasome is an inducible type of proteasome that plays crucial roles in homeostasis, immunity, and inflammation. The immunoproteasome incorporates three catalytic β subunits; LMP2, MECL1, and LMP7 which replace the proteasome subunits β1, β2, and β5, respectively, in the presence of inflammatory cytokines. We previously showed that mTORC1 promotes immunoproteasome formation, indicating that nutritional status regulates immunoproteasome abundance. Despite its strong relevance to disease, the functions of the immunoproteasome remain poorly understood. In this study we sought to illuminate the functions of the immunoproteasome in hepatocyte metabolism through multiplexed proteomics using LMP2-/- primary mouse hepatocytes. Through Reactome Pathway and GO Biological Process analysis, we found that LMP2 depletion in primary hepatocytes reduces the abundance of proteins involved in glucose metabolism and detoxification of reactive oxygen species while increasing abundance of proteins involved in mitochondrial biogenesis, TCA cycle and electron transport chain, mitochondrial and peroxisomal fatty acid oxidation, and the unfolded protein response. Under interferon γ (IFNγ)-stimulated conditions, proteins in keratinization and apoptosis were reduced suggesting reduced inflammation in LMP2-/- hepatocytes, and proteins in fatty acid and amino acid metabolism are increased. Combined, these results suggest that the immunoproteasome might play important roles in hepatic metabolism.


A. Edmund: None. C. Yun: None. D. Kim: None.


American Diabetes Association (1-19-IBS-071 to D-H.K.); National Institutes of Health (5T32DK007203-40)

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