Background and Aims: The risk factors of cholelithiasis have not been clearly identified, especially for total cholesterol. Here, we try to identify these causal risk factors. Approach and Results: We obtained genetic variants associated with the exposures at the genome‐wide significance (p < 5 × 10⁻⁸) level from corresponding genome‐wide association studies. Summary‐level statistical data for cholelithiasis were obtained from FinnGen and UK Biobank (UKB) consortia. Both univariable and multivariable Mendelian randomization (MR) analyses were conducted to identify causal risk factors of cholelithiasis. Results from FinnGen and UKB were combined using the fixed‐effect model. In FinnGen, the odds of cholelithiasis increased per 1‐SD increase of body mass index (BMI) (OR = 1.631, p = 2.16 × 10⁻⁷), together with body fat percentage (OR = 2.108, p = 4.56 × 10⁻³) and fasting insulin (OR = 2.340, p = 9.09 × 10⁻³). The odds of cholelithiasis would also increase with lowering of total cholesterol (OR = 0.789, p = 8.34 × 10⁻⁵) and low‐density lipoprotein–cholesterol (LDL‐C) (OR = 0.792, p = 2.45 × 10⁻⁴). However, LDL‐C was not significant in multivariable MR. In UKB, the results of BMI, body fat percentage, total cholesterol, and LDL‐C were replicated. In meta‐analysis, the liability to type 2 diabetes mellitus and smoking could also increase the risk of cholelithiasis. Moreover, there were no associations with other predominant risk factors. Conclusions: Our MR study corroborated the risk factors of cholelithiasis from previous MR studies. Furthermore, lower total cholesterol level could be an independent risk factor.

Objective: Different serum lipids and lipid-modifying targets should affect the risk of cholelithiasis differently, however, whether such effects are causal is still controversial and we aimed to answer this question. Design: We prospectively estimated the associations of four serum lipids with cholelithiasis in UK Biobank using the Cox proportional hazard model, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Furthermore, we estimated the causal associations of the genetically predicted serum lipids with cholelithiasis in Europeans using the Mendelian randomisation (MR) design. Finally, both drug-target MR and colocalisation analyses were performed to estimate the lipid-modifying targets’ effects on cholelithiasis, including HMGCR , NPC1L1 , PCSK9 , APOB, LDLR, ACLY, ANGPTL3, MTTP, PPARA, PPARD and PPARG . Results: We found that serum levels of LDL-C and HDL-C were inversely associated with cholelithiasis risk and such associations were linear. However, the serum level of TC was non-linearly associated with cholelithiasis risk where lower TC was associated with higher risk of cholelithiasis, and the serum TG should be in an inverted ‘U-shaped’ relationship with it. The MR analyses supported that lower TC and higher TG levels were two independent causal risk factors. The drug-target MR analysis suggested that HMGCR inhibition should reduce the risk of cholelithiasis, which was corroborated by colocalisation analysis. Conclusion: Lower serum TC can causally increase the risk of cholelithiasis. The cholelithiasis risk would increase with the elevation of serum TG but would decrease when exceeding 2.57 mmol/L. The use of HMGCR inhibitors should prevent its risk.

Data for p53 mutation in prostate cancer in The Cancer Genome Atlas database revealed that >85% of p53 mutations occurred in the p53 DNA binding domain. These mutations not only severely damage the function of the p53 protein, but also reduce the disease‑free survival of patients. Peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α) is involved in the regulation of mitochondrial function and is highly expressed in prostate cancer PC3 and DU145 cells with p53 deletion or mutation. However, whether p53 negatively regulates PGC‑1α in prostate cancer cells remains to be elucidated. In the present study, p53 overexpression was induced in prostate cancer PC3 cells. Subsequently, the expression levels of PGC‑1α and alterations to mitochondrial function were assessed. Moreover, PGC‑1α was activated in prostate cancer PC3 cells using ZLN005 to investigate alterations to mitochondrial function and cell apoptosis. The present study revealed that p53 decreased the expression and nuclear localization of the PGC‑1α protein and induced mitochondrial dysfunction. Activation of PGC‑1α partially reversed p53‑mediated mitochondrial dysfunction. Inhibition of the p53/PGC‑1α pathway on mitochondrial biogenesis and fission‑/fusion‑associated gene and protein expression were associated with mitochondrial dysfunction. p53/PGC‑1α‑mediated mitochondrial dysfunction promoted apoptosis of PC3 prostate cancer cells. The results indicated that PGC‑1α is an essential target of p53‑induced apoptosis in prostate cancer cells and indicated that targeting PGC‑1α may provide a new therapeutic strategy for prostate cancer.