SeP is elevated in NAFLD and participates in NAFLD pathogenesis through AMPK/ACC pathway

Background: Non-alcoholic fatty liver disease (NAFLD) is prevalent chronic liver diseases with unknown mechanism and no curative treatment. Hepatokines have demonstrated important role in NAFLD pathogenesis but, role of selenoprotein P (SeP) in NAFLD is unknown. Methods: We included NAFLD patients as well as equivalent healthy controls and collected demographic data, medical history and general information. Serum sample was sent for blood routine, biochemical study and also SeP by ELISA. NAFLD in vivo and in vitro models were generated with high fat diet and palmitic acid, respectively. siRNA, overexpression plasmid and purified protein of SeP were used to manipulate SeP level in hepatocyte. qRT-PCR, Western Blot and quantative triglyceride measurement were used to evaluated corresponding effect. Findings: A total of 79 NAFLD patients and 79 healthy controls were included in this case-control study. SeP is elevated in NAFLD patients (P < 0.05). With elevating level of SeP, NAFLD prevalence and detecting rate increases (P < 0.05). As NAFLD aggravated, serum SeP increases. Correlation analysis demonstrates that SeP is positively associated with NAFLD risk factors BMI, ALT, AST, GGT and serum uric acid (P < 0.05). Both NAFLD in vivo and in vitro models, SeP protein level is higher in liver. siRNA of SEPP1 inhibited TG accumulation by activating AMPK/ACC, and overexpression of SEPP1 with plasmid or recombinant protein both aggravated lipid accumulation and inhibited AMPK/ACC phosphorylation. Interpretation: SeP expression is activated in NAFLD and excerbated NAFLD through AMPK/ACC pathway, providing insight into new diagnostic, therapeutic target in NAFLD. Funding Statement: The authors stated: "None." Declaration of Interests: The authors declare there are no conflicting financial interests. Ethics Approval Statement: The study protocol was approved by the Hospital Ethics Committee and performed in accordance with Declaration of Helsinki. All persons gave their informed consent prior to their inclusion in the study and study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Study protocol has been approved by ethical committee of our hospital and conforms to Animal Research: Reporting of in vivo Experiments (ARRIVE) guidelines.