The ubiquitin proteasome system (UPS) is important in maintaining protein homeostasis. NFE2-related factor 1 (Nrf1), a transcription factor in the cap “n” collar (CNC) basic leucine zipper family, regulates expression of cytoprotective genes. It was previously shown that liver-specific knockout of Nrf1 (Nrf1LKO) leads to hepatic cell death, steatohepatitis and cancer. However, the mechanisms underlying these pathologies are not clear. Here, we report that Nrf1 is critical for proteasome gene expression in the liver. Liver-specific knockout of Nrf1 results in impaired basal and induced expression of proteasome genes, and diminished proteasome activity in hepatocytes. In addition, our findings demonstrated that ER stress signaling pathway was also activated in Nrf1LKO livers. Inhibition of proteasome activity leads to ER stress in Nrf1-deficient hepatocytes, prompting the development of steatosis in the liver. Our results indicate that Nrf1 plays an integral role in the maintenance of proteasome function in hepatocytes and in the prevention of liver steatosis development. Moreover, these results highlight an association between proteasome dysfunction, ER stress and steatosis.

a b s t r a c tHerpud1 is an ER-localized protein that contributes to endoplasmic reticulum (ER) homeostasis by participating in the ER-associated protein degradation pathway. The Nrf1 transcription factor is important in cellular stress pathways. We show that loss of Nrf1 function results in decreased Herpud1 expression in cells and liver tissues. Expression of Herpud1 increases in response to ER stress, but not in Nrf1 knockout cells. Transactivation studies show that Nrf1 acts through antioxidant response elements located in the Herpud1 promoter, and chromatin immunoprecipitation demonstrates that Herpud1 is a direct Nrf1 target gene. These results indicate that Nrf1 is a transcriptional activator of Herpud1 expression during ER stress, and they suggest Nrf1 is a key player in the regulation of the ER stress response in cells.

A B S T R A C TThe Nrf1 (Nuclear factor E2-related factor 1) transcription factor performs a critical role in regulating cellular homeostasis. Using a proteomic approach, we identified Host Cell Factor-1 (HCF1), a co-regulator of transcription, and O-GlcNAc transferase (OGT), the enzyme that mediates protein O-GlcNAcylation, as cellular partners of Nrf1a, an isoform of Nrf1. Nrf1a directly interacts with HCF1 through the HCF1 binding motif (HBM), while interaction with OGT is mediated through HCF1. Overexpression of HCF1 and OGT leads to increased Nrf1a protein stability. Addition of O-GlcNAc decreases ubiquitination and degradation of Nrf1a. Transcriptional activation by Nrf1a is increased by OGT overexpression and treatment with PUGNAc. Together, these data suggest that OGT can act as a regulator of Nrf1a.

Introduction:We evaluated complementary and alternative medicine (CAM) use among a medically underserved, predominately Hispanic community at the University of California Irvine Family Health Center, a federally qualified health center.Methods: A cross-sectional, anonymous survey assessed patient use of, interest in, and communication preferences concerning CAM.Results: The 150 respondents primarily self-identified as Hispanic (74%), were born outside the United States (55%), were medically insured (56%), and had a high school education or less (55%). Of these respondents, 63% used at least 1 type of CAM; the most commonly used were: vitamins/supplements (32%), herbal medicine (29%), dietary/nutritional therapy (26%), massage (24%), meditation/ relaxation (15%) and chiropractic (11%). Therapies that patients most desired to see provided at the clinic included massage, healthier cooking, guidance on herbs/supplements, and diet/nutrition. Among respondents, 61% were comfortable disclosing CAM use to physicians, 58% agreed physicians should have basic knowledge of CAM, and 47% desired that physicians ask about CAM use.

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