Effect of Alternate day fasting over Metabolic dysfunction-associated steatohepatitis in adult offspring of dams exposed to cafeteria diet during pregnancy and lactation.

IF 3.7 3区医学 Q2 GASTROENTEROLOGY & HEPATOLOGY

Annals of hepatology Pub Date : 2025-04-01 DOI:10.1016/j.aohep.2025.101803

Martín G. García-Juárez, Tania G. Heredia-Torres, Daniel Arellanos-Soto, Blanca E. Álvarez-Salas, Alberto Camacho-Morales, Ana María G. Rivas-Estilla

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Abstract

Introductions and Objectives

Metabolic dysfunction-associated steatohepatitis (MASH) is a liver disease characterized by lipid accumulation and inflammation that can be exacerbated by cafeteria diets (CAF) exposition during pregnancy and lactation, whereas Alternate day fasting (ADF) improves metabolic parameters. Evaluate the effect of ADF and CAF maternal programming on MASH-associated markers in the offspring.

Materials and Patients

To assess the effect of maternal programming, we elaborated a mice model using 8-week C57BL6 females exposed to a CAF (cafeteria) diet (39% carbs, 49% fats, 12% proteins and sodium 231.8 mg) during 3 weeks of mating, 3 weeks of gestation and 3 weeks of lactation. For maternal programming control, we fed females with a Chow or control diet (57% carbs, 13% fats, 30% proteins and sodium 105 mg) during 3 weeks of mating, 3 weeks of gestation and 3 weeks of lactation. After weaning, the offspring were fed a control diet until they were 8 weeks old. They were then divided into four groups (Control n=8, Control + ADF n=8, CAF n=8, CAF+ ADF n=8) and an alternate day Fasting (ADF) protocol was initiated for 5 weeks. At the end of the fasting protocol, plasma samples were taken and beta-hydroxybutyrate (BHB) concentration was measured; in addition, samples of the left lateral lobe of the liver were taken at slaughter to evaluate by qPCR the effect of intermittent fasting on the expression of metabolic function markers involved during MASH: fibrosis (TGFβ, Col1a1), steatosis (PLIN2, ApoB100, Mylcd, PPARPα) and inflammation (Mcp-1).

Results

Groups treated with ADF showed an increase in plasma BHB concentration of 400 μmol compared to non-fasted groups. However, no significant difference was found between the control +ADF and CAF + ADF groups, so no effect of maternal programming with CAF diet on BHB production was observed. Additionally, the relative expression of mRNA from fibrosis-associated markers such as Col1a1 showed an 84% decrease in the CAF maternal programming model, 80% in the Control + ADF group and 88% in the CAF + ADF model with respect to control. Levels of mRNA-Plin2, involved in lipid droplet formation, decreased by 57% in the CAF group, 48% in Control +ADF and 79% in CAF+ADF. On the other hand, mRNA-Mcp-1 levels (chemokine) showed a decrease of 14.36% in CAF, 46.42% in Control + ADF and 62.68% in CAF+ ADF with respect to control.

Conclusions

The model of alternate-day fasting (ADF) showed an increased plasma BHB, but we did not observe a maternal programming effect on the concentration of betahydroxybutyrate. Interestingly, maternal programming and ADF reduce the expression of MASH-associated markers involved in fibrosis, lipid droplet formation and inflammation in this mouse model.

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隔日禁食对妊娠期和哺乳期暴露于自助饮食的母鼠成年后代代谢功能障碍相关脂肪性肝炎的影响。

代谢功能障碍相关脂肪性肝炎（MASH）是一种以脂质积累和炎症为特征的肝脏疾病，妊娠和哺乳期自助饮食（CAF）可加重脂质积累和炎症，而隔日禁食（ADF）可改善代谢参数。评估ADF和CAF母体编程对后代mash相关标记的影响。为了评估母体编程的影响，我们制作了一个小鼠模型，将8周的C57BL6雌性小鼠在交配3周、妊娠3周和哺乳3周期间暴露于CAF（食堂）饮食（39%碳水化合物、49%脂肪、12%蛋白质和231.8 mg钠）。为了控制雌性的编程，我们在交配3周、妊娠3周和哺乳期3周内给雌性喂食Chow或对照饮食（57%碳水化合物、13%脂肪、30%蛋白质和105毫克钠）。断奶后，给幼崽喂食控制饮食，直到它们8周大。然后将他们分为四组（Control n=8, Control + ADF n=8, CAF n=8, CAF+ ADF n=8），并开始隔日禁食（ADF）方案，为期5周。禁食结束时，取血浆样品，测定β -羟基丁酸（BHB）浓度；此外，在屠宰时取肝脏左外侧叶样本，通过qPCR评估间歇性禁食对MASH过程中代谢功能标志物表达的影响：纤维化（TGFβ, Col1a1），脂肪变性（PLIN2, ApoB100, Mylcd, PPARPα）和炎症（Mcp-1）。结果ADF处理组血浆BHB浓度较未禁食组升高400 μmol。然而，对照组+ADF组和CAF + ADF组之间没有发现显著差异，因此未观察到母体规划CAF日粮对BHB产量的影响。此外，与对照组相比，来自纤维化相关标记物（如Col1a1）的mRNA的相对表达量在CAF母体编程模型中下降了84%，在Control + ADF组中下降了80%，在CAF + ADF模型中下降了88%。参与脂滴形成的mRNA-Plin2水平在CAF组下降了57%，在Control +ADF组下降了48%，在CAF+ADF组下降了79%。另一方面，趋化因子mRNA-Mcp-1水平在CAF组较对照组下降14.36%，在Control + ADF组下降46.42%，在CAF+ ADF组下降62.68%。结论ADF模型小鼠血浆BHB升高，但未观察到母体编程对β -羟基丁酸盐浓度的影响。有趣的是，在该小鼠模型中，母体编程和ADF降低了参与纤维化、脂滴形成和炎症的mash相关标志物的表达。

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来源期刊

Annals of hepatology 医学-胃肠肝病学

CiteScore

7.90

自引率

2.60%

发文量

183

审稿时长

4-8 weeks

期刊介绍： Annals of Hepatology publishes original research on the biology and diseases of the liver in both humans and experimental models. Contributions may be submitted as regular articles. The journal also publishes concise reviews of both basic and clinical topics.