Lactoferrin promotes bile acid metabolism and reduces hepatic cholesterol deposition by inhibiting the farnesoid X receptor (FXR)-mediated enterohepatic axis.

BACKGROUND: Lactoferrin (LF) is a multifunctional glycoprotein that can regulate lipid metabolism, lower cholesterol, reduce body weight, and prevent atherosclerosis. Bile acid (BA) metabolism plays an important role in removing excess cholesterol from the body. However, studies on the effects of LF on BA metabolism are limited and inconsistent. METHODS: Male C57BL/6J mice aged 6-8 weeks were fed with a normal diet (control group), high-fat/high-cholesterol diet containing cholate (HFCCD group), or HFCCD and 1.0% LF in drinking water (LF group) for 8 weeks. Serum and hepatic lipid profiles, and glucose tolerance were measured. Fecal BA composition was determined through ultra-high performance liquid chromatography-tandem mass spectrometry. The gene expression of BA synthase in the liver and farnesoid X receptor (FXR)-mediated BA negative feedback regulation pathway in the liver and ileum were analyzed via RNA analysis. RESULTS: HFCCD resulted in abnormal cholesterol levels in the serum and liver. LF intervention significantly increased the serum high-density lipoprotein cholesterol level by 24.9% and decreased the hepatic total cholesterol content by 26%. LF treatment significantly increased the BA content per gram by 109.8%, the total amount of BA excretion by 153.5% and conjugated BAs by 87.6% in the feces. Furthermore, LF upregulated the expression of the hepatic sterol 12α-hydroxylase (CYP8B1) gene, which expresses important enzymes in the classical pathway of BA synthesis, and the bile acid-CoA amino acid N-acetyltransferase (BAAT) gene, which is responsible for the formation of conjugated BAs. The FXR-mediated pathways in the enterohepatic axis, including FXR, fibroblast growth factor 15, and fibroblast growth factor receptor 4, were inhibited by LF. CONCLUSIONS: LF ameliorated hepatic cholesterol deposition in mice fed with a high-fat and high cholesterol diet containing cholate. LF elevated the conjugated BA level, inhibited the ileum FXR and FXR-mediated enterohepatic axis, and increased BA synthesis and excretion.

Lactoferrin Alleviates the Progression of Atherosclerosis in ApoE-/- Mice Fed with High-Fat/Cholesterol Diet Through Cholesterol Homeostasis.

Lactoferrin (LF) is a multifunctional glycoprotein and has beneficial effects on the regulation of lipid metabolism. However, whether LF supplementation alleviates the development of atherosclerosis (AS) remains unclear. In the present study, all of 48 male Apolipoprotein E-/- mice were fed with high-fat diet with 1.25% added cholesterol and divided to four treatment groups with either distilled water (HFCD), LF solutions at 2 mg/mL (low LF), 10 mg/mL (middle LF or MLF), or 20 mg/mL (high LF or HLF) for 12 weeks. Oral glucose tolerance tests (OGTT) were performed at weeks 0, 4, 8, and 12. At the end of the experiment, lipids in serum, liver, and feces were determined. The livers, whole aortas, and aortic sinuses were pathologically examined. The protein expression of factors related to cholesterol synthesis, absorption, and excretion were detected through western blot. No significant difference in body weight, food intake, and OGTT was observed among the four groups. Compared with the HFCD group, the MLF and HLF groups had significantly decreased serum and hepatic cholesterol levels and significantly increased fecal cholesterol contents. LF alleviated the hepatic steatosis and lipid droplet, especially in the MLF group. LF also significantly decreased the average lesion areas in the whole aorta, especially in the MLF group. On the other hand, LF downregulated hepatic protein expression of HMG-CoA reductase (the rate-limiting enzyme in cholesterol synthesis) and upregulated cholesterol 7-alpha hydroxylase (the rate-limiting enzyme in bile acid synthesis from cholesterol). LF also downregulated the intestinal expression of Niemann-Pick C1-like 1 protein, which is known to bind to a critical mediator of cholesterol absorption. In conclusion, LF supplementation alleviates the AS in mice on HFCD likely by reducing the synthesis and absorption of cholesterol and increasing cholesterol excretion.

Fasting blood glucose levels and prognosis in patients with non-small-cell lung cancer: a prospective cohort study in China.

PURPOSE: Non-small-cell lung cancer (NSCLC) is the most diagnosed lung cancer and is associated with poor prognosis. This study aimed to analyze whether fasting blood glucose (FBG) levels could provide prognostic information in Chinese patients with NSCLC, using the Suzhou Lung Cancer Survival study. PATIENTS AND METHODS: A prospective cohort study of adult patients with primary NSCLC was performed. The patients who were hospitalized between January 2016 and April 2018 in two hospitals affiliated with Soochow University were recruited. Patient information, including lifestyle habits and clinical and laboratory data, were collected through face-to-face interviews and evaluation of medical records. Follow-up was initiated from the date of patient enrollment until May 8, 2018 or until patient death. The long-term survival of patients was assessed every 6 months. Patient vital status was confirmed by using hospital records, telephone interview, or local death registration system. Cox proportional hazards regression was used to estimate hazard ratio and 95% confidence interval (CI) for death, with adjustment for cancer stage, medical treatments, smoking, and other potential confounders. RESULTS: A total of 387 patients were included in the analysis, and the numbers (percentages) of patients with stages I, II, III, and IV NSCLC were 53 (13.7%), 41 (10.6%), 64 (16.5%), and 215 (55.6%), respectively. The median duration of follow-up was 19.1 months. Compared with patients in the second tertile of FBG, the HRs for mortality were 2.16 (95% CI: 1.26-3.73) and 1.87 (95% CI: 1.03-3.42) for those in the lowest one and diabetic group, respectively. Subgroup analysis according to various patient characteristics confirmed these associations. CONCLUSION: Diabetes and low FBG could be important predictors of death in patients with NSCLC. Maintaining appropriate blood glucose levels may improve prognosis in patients with NSCLC.