The Salivary Protein PSP/BPIFA2 Prevents Non-Alcoholic Fatty Liver Disease

Objectives: BPIFA2 (BPI-fold family A member 2; former names: Parotid Secretory Protein, PSP, SPLUNC2, C20orf70) is a secretory protein that is highly expressed in salivary glands and predicted to be structurally related to lipid and LPS-binding proteins (BPI-fold containing family). We have previously reported that BPIFA2 binds lipopolysaccharide (LPS) and now tested its role in Bpifa2^-/- knockout (BPIFA2-KO) mice.

Methods: BPIFA2-KO-mice were obtained from KOMP (UC-Davis). Saliva was analyzed by immunoblot and contact-angle; Insulin (ELISA), glucose (glucometer), lipids (clinical assays) were determined in fasting blood/serum. Hepatic gene-expression determined by RT-qPCR, Liver and intestine histology determined on H&E-stained sections. Mice were fed LPS in drinking water for 24h and intestinal motility determined at 6-24h.

Results: BPIFA2-KO-mouse saliva lacked BPIFA2 with significant reduction in surfactant activity. BPIFA2-KO-mice lacked dental /oral anomalies and consumed normal amounts of dry-powdered food. Blood glucose was normal, fasting insulin was increased in male BPIFA2-KO-mice. Serum triglycerides and VLDL were decreased in male BPIFA2-KO-mice. Hepatic lipogenic gene-expression was upregulate; fatty acid oxidation genes were downregulated in BPIFA2-KO-mice with substantial lipid droplet accumulation in male BPIFA2-KO-mouse livers (hepatic steatosis). Proximal small intestine of BPIFA2-KO-mice exhibited damage to villus structure with shorter, less-dense villi. Since BPIFA2 binds LPS but not the major dietary lipids triglyceride/diacylglycerol/cholesterol, we tested if BPIFA2-ablation affects LPS action in the intestine. BPIFA2-KO-mice were significantly more susceptible to ingested LPS than wild-type mice, as determined by fecal pellet output.

Conclusions: The results suggest that BPIFA2 provides a protective effect against LPS in the GI tract to prevent non-alcoholic fatty liver disease in animals fed a normal diet. The finding that a salivary protein directly affects the health of the intestine and liver by protecting them from the toxic effects of LPS is unexpected and points to an extra-oral function for saliva in the GI tract.