Role of Inflammatory Factors in Mediating the Effect of Lipids on Nonalcoholic Fatty Liver Disease: A Two-Step, Multivariable Mendelian Randomization Study

Abstract

Aims/hypothesis: 20–80% of Nonalcoholic Fatty Liver Disease (NAFLD) have been observed to have dyslipidemia. Nevertheless, the probable mechanism of dyslipidemia’s effect on NAFLD remains unclear. Mendelian randomization (MR) was utilized to investigate the relationship between lipids, inflammatory factors, and NAFLD; and also, to determine the proportion mediated by interleukin-17(IL-17) and interleukin-1β(IL-1β) for the effect between lipids and NAFLD. Methods: Summary statistics of traits were obtained from the latest and largest genome-wide association study (GWAS). The UK Biobank provided a summary of lipid statistics, which comprised up to 500,000 participants of European descent. And NAFLD GWAS summary statistics were obtained from the FinnGen Biobank which included a total sample size of 218,792 participants of European ancestry. In order to gain an overall picture of how lipids affect NAFLD, MR with two samples was carried out. Multivariable MR determined lipids direct effects on NAFLD after adjusting for inflammatory factors, namely IL-1β, interleukin-6(IL-6), interleukin-16(IL-16), IL-17, and interleukin-18(IL-18); those lipids comprise HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TGs), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB). For the purpose of determining the MR impact, an inverse variance weighted (IVW) meta-analysis of each Wald Ratio was carried out, while other methods were also performed for sensitivity analysis. Results: We discovered a positive association between genetically predicted TGs levels and a 45.5% elevated risk of NAFLD, while genetically predicted IL-1β [(IVW: OR 1.315 (1.060–1.630), p = 0.012) and IL-17 [(IVW: OR 1.468 (1.035–2.082), p = 0.032] were positively associated with 31.5% and 46.8% increased risk of NAFLD, respectively. Moreover, TG was positively associated with 10.5% increased risk of IL-1β and 17.3% increased risk of IL-17. The proportion mediated by IL-17 and IL-1β respectively and both was 2.6%, 3.1%, 14.1%. Conclusion: Genetically predicted TGs, IL-1β, and IL-17 were positively associated with increased risk of NAFLD, with evidence that IL-1β and IL-17 mediated TGs effect upon NAFLD risk. It indicated that early diet management, weight management, lipid-lowering and anti-inflammatory treatment should be carried out for patients with hyperlipidemia to prevent the NAFLD.

Lead exposure exacerbates liver injury in high-fat diet-fed mice by disrupting the gut microbiota and related metabolites

“…52 Recent studies have reported that the pro-inflammatory factor IL-1β promotes an increased risk of NAFLD by mediating TG. 53 These findings further support our results that Pb exposure exacerbates hepatic lipid accumulation in HFD mice and that this may be associated with the upregulation of inflammatory genes such as IL-1β and TNF-α. Therefore, Pb-aggravated liver lipid accumulation in HFD mice may affect fatty acid metabolism and inflammation levels by mediating the metabolites SCFAs and LPSs.…”

Lipid-lowering drugs affect lung cancer risk via sphingolipid metabolism: a drug-target Mendelian randomization study

“…To explore the mediating effect of sphingolipid metabolites regarding the effect of LLDs on lung cancer risk, a two-step MR analysis was performed. The proportion mediated by sphingolipid metabolites was calculated using the following formula ( Chen et al, 2022 ; Zhao et al, 2022 ): , where β1 represents the estimated effect of LLDs on sphingolipid metabolites, β2 represents the estimated effect of sphingolipid metabolites on lung cancer, and β3 represents the estimated direct effect of LLDs on lung cancer. The product of β1 and β2 is considered the indirect effect, while (β3 + β1 × β2) represents the total effect.…”

“…The product of β1 and β2 is considered the indirect effect, while (β3 + β1 × β2) represents the total effect. The proportion is calculated when β1, β2, and β3 exhibit statistical significance, as this quantifies the proportion of mediation by sphingolipid metabolites within the total effect ( Chen et al, 2022 ). To account for multiple statistical tests and reduce false-positive results, we controlled the false discovery rate (FDR) using the Benjamini–Hochberg method.…”

The state of the cytokine profile in pregnant women with non-alcoholic fatty liver disease at the stage of non-alcoholic steatohepatitis with varying degrees of comorbid obesity under the influence of the developed complex therapy program

“…An overload of toxic lipids, mainly free fatty acids, causes oxidative stress and induces specific signals that cause hepatocyte apoptosis as the predominant mechanism of cell death in NASH, correlating with the degree of liver inflammation and fibrosis [6,7,10]. Systemic inflammation is also an important pathogenetic trigger of endothelial dysfunction, which is associated with the activation of IL-6 and TNF-α cytokines in obese patients [13,15]. A large amount of placental TNF-α is released during pregnancy into the maternal bloodstream (94 %) and less into the fetal bloodstream (6 %) [11,15,21].…”

“…Systemic inflammation is also an important pathogenetic trigger of endothelial dysfunction, which is associated with the activation of IL-6 and TNF-α cytokines in obese patients [13,15]. A large amount of placental TNF-α is released during pregnancy into the maternal bloodstream (94 %) and less into the fetal bloodstream (6 %) [11,15,21]. There is a positive correlation between the level of TNF-α and placental dysfunction, depending on its severity [21].…”