Shuang-Zhe Lin

Background: This study aimed to investigate the causal association between mental disorders and nonalcoholic fatty liver disease (NAFLD; now termed metabolic dysfunction‐associated steatotic liver disease, MASLD) using Mendelian randomization (MR). Methods: A bidirectional two‐sample MR approach was employed to evaluate the causal relationship between NAFLD and eight mental disorders: major depression, anxiety, bipolar disorder, schizophrenia, autism, post‐traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), and eating disorders. The inverse‐variance weighted (IVW) method was utilized to estimate causal effects, supported by MR‐CAUSE and other sensitivity analyses to address pleiotropy and heterogeneity. Instrumental variables from genome‐wide association studies were applied, and initial associations were examined using linkage disequilibrium score (LDSC) regression analysis. Furthermore, mediation analysis was conducted to identify potential mediators. Results: The MR analysis revealed significant positive associations between NAFLD occurrence and major depression (odds ratio [OR] = 1.294, p = 0.003), bipolar disorder (OR = 0.895, p = 0.004), and autism (OR = 1.118, p = 0.005). However, only the putative causal association of major depression on NAFLD remained statistically significant in further validation, including MR‐CAUSE and sensitivity analyses, and was not attributable to linkage disequilibrium. No causal effect of NAFLD on mental disorders was found in reverse MR analysis. In LDSC regression, significant positive associations with NAFLD occurrence were observed for major depression (Rg = 0.538, p = 1.36 E − 07), ADHD (Rg = 0.798, p = 1.10 E − 08), and PTSD (Rg = 0.579, p = 0.009). Mediation analysis identified body mass index (39.33%, p = 0.017), waist‐to‐hip ratio (8.09%, p = 0.026), triglycerides (39.33%, p = 0.017), and serum concentration of large very low‐density lipoprotein (VLDL) particles (8.76%, p = 0.032) as mediators of the causal effect of major depression on NAFLD occurrence. Conclusion: This study suggests a potential causal link between major depression and the development of NAFLD, underscoring the importance of considering major depression in the management of NAFLD patients.

Background and Aims: Both nonalcoholic fatty liver disease (NAFLD) and cholelithiasis are highly prevalent hepatobiliary diseases with risk of progression into severe outcomes. Considering the close relationship between liver and gallbladder in anatomy and physiology, a potential causal relationship between NAFLD and cholelithiasis has been speculated.Methods: Mendelian randomization (MR) was employed using genome‐wide association study (GWAS) summary statistics in Million Veteran Program (MVP) for NAFLD, and statistics in UK biobank for cholelithiasis.Results: Our results demonstrate that NAFLD has a causal effect on cholelithiasis risk (OR, 1.003; 95%CI, 1.000–1.006; p = 0.03). We also performed the sensitivity analysis and heterogeneity test to ensure the accuracy of outcome and avoid the reverse causality.Conclusion: NAFLD should be regarded as a potential pathogenic factor in pathogenesis study of cholelithiasis, and be considered in assessment and treatment of cholelithiasis.

Background: Prolyl endopeptidase (PREP) is a serine endopeptidase that regulates inflammatory responses. PREP inhibitors can reduce hepatocyte lipid accumulation and may participate in the progression of nonalcoholic fatty liver disease (NAFLD). We investigated whether disruption of PREP regulates hepatic steatosis and inflammation in mice with NAFLD. Methods: Wild-type and PREP gene disrupted mice were randomly divided into low-fat diet wild-type (LFD-WT), high-fat diet wild-type (HFD-WT), low-fat diet PREP disruption (LFD-PREP^gt), and high-fat diet PREP disruption (HFD-PREP^gt) groups. Animals were euthanized at the endpoint of 32 weeks. The NAFLD activity score and number of inflammatory cells were determined by hematoxylin-eosin staining and immunohistochemical staining of liver tissue. The expression levels of inflammation- and lipid metabolism-associated genes in the liver and serum were detected by quantitative reverse transcription PCR, mass spectrometry, or enzyme-linked immunosorbent assay. Results: The body weight and epididymal fat tissue index of the HFD-PREP^gt mice were significantly decreased compared with that of the HFD-WT mice. Moreover, the NAFLD activity score and liver function were attenuated in the HFD-PREP^gt mice. Fat accumulation and the level of expression of mRNAs associated with lipid metabolism and proinflammatory responses were improved in the HFD-PREP^gt mice. The number of CD68-positive cells in liver tissue and the serum levels of inflammation-associated factors were significantly decreased in the HFD-PREP^gt mice compared with those in the HFD-WT mice. Further mechanistic investigations indicated that the protective effect of PREP disruption on liver inflammation was associated with the suppressed production of matrix metalloproteinases (MMPs) and proline-glycine-proline (PGP) and the inhibition of neutrophil infiltration. Conclusions: Loss of PREP lowers the severity of hepatic steatosis and inflammatory responses in a high-fat diet-induced nonalcoholic steatohepatitis model. PREP inhibition may protect against NAFLD.

Despite the widespread use of vaccines and antiviral drugs, approximately 350‐400 million patients with chronic hepatitis B (CHB) remain worldwide, who carry high risk of cirrhosis and liver carcinoma. Moreover, owing to improvements in global living standards and lifestyle changes, non‐alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease. Coexistence of NAFLD and CHB is commonly observed, especially in Asian CHB populations; however, little is known regarding the relationship between these two diseases as comorbidities. In this review, we summarize recent advances in clinical and basic researches related to the underlying mutual interactions, as well as potential animal models to facilitate further investigation.