Causal associations between intermediate very-low-density lipoprotein cholesterol-to-total lipids ratio and peptic ulcer:A bidirectional Mendelian randomization study

BACKGROUND Previous epidemiologic investigations have consistently demonstrated a strong association between the ratio of cholesterol to total lipids in medium very-lowdensity lipoprotein(VLDL)and the occurrence of peptic ulcers(PU).However,the precise causal relationship between these factors remains ambiguous.Consequently,this study aims to elucidate the potential correlation between the ratio of cholesterol to total lipids in medium VLDL and the incidence of peptic ulcer.AIM To investigate the ratio of cholesterol to total lipids in medium very-low-density lipoprotein(VLDL)association with PU via genetic methods,guiding future clinical research.METHODS Genome-wide association study(GWAS)datasets for the ratio of cholesterol to total lipids in intermediate VLDL and peptic ulcer were retrieved from the IEU OpenGWAS project(https://gwas.mrcieu.ac.uk).For the forward Mendelian randomization(MR)analysis,72 single nucleotide polymorphisms(SNPs)were identified as instrumental variables.These SNPs were selected based on their association with the ratio of cholesterol to total lipids in intermediate VLDL,with peptic ulcer as the outcome variable.Conversely,for the inverse MR analysis,no SNPs were identified with peptic ulcer as the exposure variable and the ratio of cholesterol to total lipids in intermediate VLDL as the outcome.All MR analyses utilized inverse variance weighted(IVW)as the primary analytical method.Additionally,weighted median and MR-Egger methods were employed as supplementary analytical approaches to assess causal effects.Egger regression was used as a supplementary method to evaluate potential directional pleiotropy.Heterogeneity and multiplicity tests were conducted using the leave-one-out method to evaluate result stability and mitigate biases associated with multiple testing.RESULTS The genetically predicted ratio of cholesterol to total lipids in medium VLDL was significantly associated with an elevated risk of peptic ulcer(IVW:OR=2.557,95%CI=1.274-5.132,P=0.008).However,no causal association of peptic ulcer with the ratio of cholesterol to total lipids in medium VLDL was observed in the inverse Mendelian randomization analysis.CONCLUSION In conclusion,our study reveals a significant association between the ratio of cholesterol to total lipids in medium VLDL and an elevated risk of peptic ulcers.However,further validation through laboratory investigations and larger-scale studies is warranted to strengthen the evidence and confirm the causal relationship between these factors.

Effects of Berberine on Hepatic Sirtuin 1-uncoupling Protein 2 Pathway in Non-alcoholic Fatty Liver Disease Rats Induced by High-fat Diet

Objective To investigate the involvement of sirtuin 1（SIRT1）-uncoupling protein 2（UCP2） pathway in the development of non-alcoholic fatty liver disease and whether berberine exerts its effects by regulating this pathway. Methods Male SD rats were divided into three groups： normal control group, high-fat diet group, and berberine supplement group. The rats in the normal control group were given normal diet while the rats in the other two groups were fed with high-fat diet. Rats in the berberine supplement group were concurrently given berberine（100 mg/kg body weight） once daily. After 16 weeks, the levels of serum, liver lipids, and serum aminotransferase were measured using an automatic biochemical analyzer. Superoxide dismutase（SOD） activity and malondialdehyde（MDA） content in the liver were measured using commercial kits. Histopathological changes of liver tissues were observed by hematoxylin and eosin（HE） staining and Oil Red O staining. The hepatic m RNA and protein levels of SIRT1 and UCP2 were assayed by reverse transcription polymerase chain reaction（RT-PCR） or Western blotting. Results Berberine supplement could significantly decrease the serum and liver lipid contents in rats fed with high-fat diet. Meanwhile, SOD level was significantly elevated, but MDA level was reduced in the liver. The results of HE and Oil Red O staining showed that the hepatic steatosis was alleviated in berberine supplement group. Furthermore, berberine induced an increase in SIRT1 expression but a decrease in UCP2 expression. Conclusion The regulation of hepatic SIRT1-UCP2 pathway may be an important mechanism by which berberine exerts the beneficial effects in NAFLD rats.

Effects of Soothing Liver and Invigorating Spleen Recipe on Lipid Metabolism Disorders in Kupffer Cells of NAFLD Rats by LXRα/SREBP-1c Signal Pathway

Objective To investigate the mechanism of lipid metabolism disorders in Kupffer cells （KCs） of non-alcoholic fatty liver disease （NAFLD） rats mediated by LXRα-SREBP-lc pathway and the interference of soothing liver and invigorating spleen recipe （SLISR） on it. Methods SD male rats were randomly divided into five groups： normal, model, soothing liver recipe （SLR）, invigorating spleen recipe （ISR）, and soothing liver and invigorating spleen recipe （SLISR） groups. The rats in treatment groups were administered for 8 weeks. The liver tissue was stained with H＆E and oil red O. The levels of hepatic lipid and blood lipid were measured by biochemical analyzer. KCs were isolated from the livers of rats to evaluate the expression of LXRα, SREBP-1 C, and FAS mRNA by real-time fluorescence quantitative PCR tests; LXRα, SREBP-1C, and FAS proteins were measured by Western blotting. Results The H＆E and oil red O staining results showed that the model rats successfully reproduced typical pathogenetic and histopathological features of NAFLD. The levels of hepatic lipid and blood lipid in the model rats were dramatically increased. Compared with the model group, the values of hepatic lipid and blood lipid in the treatment groups were significantly ameliorated （P〈 0.05, 0.01 ）. The yields of purified KCs from each rat were 2×10^7-3×10^7. The viability of KCs was higher than 95%, with the purity over 90.18%. Compared with the model group, the expression of LXRα, SREBP-1C, and FAS mRNA and proteins was decreased in all treatment groups, especially in the SLR group （P〈 0.05）. Conclusion SLISR may protect liver against injury included by lipid metabolism disorders in KCs through LXRα/ SREBP-1 c signaling pathway, which may be an important mechanism for the prevention and treatment of NAFLD.