Role of endoplasmic reticulum stress in hepatic glucose and lipid metabolism and therapeutic strategies for metabolic liver disease

Zheng, Wenxiang; Sun, Qi; Li, Lanlan; Cheng, Yi; Chen, Yalin; Lv, Ming; Xiang, Xinxin

doi:10.1016/j.intimp.2022.109458

Cited by 12 publications

(6 citation statements)

References 128 publications

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“…ER stress plays an important role in the occurrence and development of NAFLD (Zheng et al, 2022 ). We used an immunoblotting assay to detect the expression of ER stress-related proteins, and found that GRP78, ATF6, PERK, IRE1a, and XBP1s in the liver of FFC diet-fed mice were significantly upregulated compared to CD mice ( Figure 4A , Supplementary Figure 3A ).…”

Section: Resultsmentioning

confidence: 99%

Nanoparticles alleviate non-alcoholic steatohepatitis via ER stress sensor-mediated intestinal barrier damage and gut dysbiosis

Zhu,

Cheng,

Tang

et al. 2024

Front. Microbiol.

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IntroductionThe gut microbiota plays an important role in the development of non-alcoholic steatohepatitis (NASH), but the underlying mechanism is unclear. It has been found that the transcription factor XBP1s plays an important role in regulating inflammation and lipid metabolism and maintaining the integrity of intestinal barrier. However, whether XBP1s modulates the development of NASH by regulating the integrity of the intestinal barrier and altering the composition of the gut microbiota remains unknown.MethodsMice fed with a fat-, fructose-, cholesterol-rich (FFC) diet for 24 weeks successfully established the NASH model, as demonstrated by significant hepatic steatosis, inflammation, hepatocyte injury and fibrosis. The profile of gut microbiota dynamically changed with the different stages of NAFLD via 16S rDNA sequencing the feces from mice fed with FFC diet for 0, 12, or 24 weeks or NASH mice treated with siRNA-loaded folic acid-modified TPGS (hereafter named FT@XBP1).ResultsNASH mice had significantly higher abundance of Firmicutes, Blautia and Bacteroides, and lower abundance of Bifidobacterium and GCA-900066575. FT@XBP1 supplementation had a significantly attenuated effect on FFC diet-induced weight gain, hepatic fat accumulation, dyslipidemia, inflammatory cytokines, ER stress and fibrosis. In particularly, FT@XBP1 modulates the composition of the intestinal flora; for example, NASH mice demonstrated higher abundance of Blautia and Bacteroides, and lower abundance of Actinobacteriota, Muribaculaceae and Bifidobacterium, which were partially restored by FT@XBP1 treatment. Mechanistically, FT@XBP1 increased the expression of ZO-1 in the intestine and had the potential to restore intestinal barrier integrity and improve antimicrobial defense to alleviate enterogenic endotoxemia and activation of inflammatory signaling pathways.DiscussionRegulation of the key transcription factor XBP1s can partially restore the intestinal microbiota structure, maintain the integrity of intestinal mucosal barrier, and prevent the progression of NASH, providing new evidence for treating NASH.

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Section: Resultsmentioning

confidence: 99%

Nanoparticles alleviate non-alcoholic steatohepatitis via ER stress sensor-mediated intestinal barrier damage and gut dysbiosis

Zhu,

Cheng,

Tang

et al. 2024

Front. Microbiol.

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“…The liver, one of the key target tissues affected by insulin, plays an important role in maintaining the metabolic homeostasis of glucose and lipid [ 29 ]. Long-term high nutrient intake led to glucolipotoxicity through inflammatory factors, reactive oxygen species, and free radicals, and contributed greatly to the metabolic disorders of the liver, such as fatty liver or diabetes [ 30 , 31 ]. The goat β-casein-derived antioxidant peptide VLPVPQK showed strong antioxidant capacity reflected by the results of ORAC and hydroxyl radical scavenging capacity.…”

Section: Discussionmentioning

confidence: 99%

The Effects and Regulatory Mechanism of Casein-Derived Peptide VLPVPQK in Alleviating Insulin Resistance of HepG2 Cells

Cao

Zhang

et al. 2023

Foods

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The liver plays a key role in keeping the homeostasis of glucose and lipid metabolism. Insulin resistance of the liver induced by extra glucose and lipid ingestion contributes greatly to chronic metabolic disease, which is greatly threatening to human health. The small peptide, VLPVPQK, originating from casein hydrolysates of milk, shows various health-promoting functions. However, the effects of VLPVPQK on metabolic disorders of the liver are still not fully understood. Therefore, in the present study, the effects and regulatory mechanism of VLPVPQK on insulin-resistant HepG2 cells was further investigated. The results showed that VLPVPQK exerted strong scavenging capacities against various free radicals, including oxygen radicals, hydroxyl radicals, and cellular reactive oxygen species. In addition, supplementation of VLPVPQK (62.5, 125, and 250 μM) significantly reversed the high glucose and fat (30 mM glucose and 0.2 mM palmitic acid) induced decrement of glucose uptake in HepG2 cells without affecting cell viability. Furthermore, VLPVPQK intervention affected the transcriptomic profiling of the cells. The differentially expressed (DE) genes (FDR < 0.05, and absolute fold change (FC) > 1.5) between VLPVPQK and the model group were mostly enriched in the carbohydrate metabolism-related KEGG pathways. Interestingly, the expression of two core genes (HKDC1 and G6PC1) involved in the above pathways was dramatically elevated after VLPVPQK intervention, which played a key role in regulating glucose metabolism. Furthermore, supplementation of VLPVPQK reversed the high glucose and fat-induced depression of AKR1B10. Overall, VLPVPQK could alleviate the metabolic disorder of hepatocytes by elevating the glucose uptake and eliminating the ROS, while the HKDC1 and AKR1B10 genes might be the potential target genes and play important roles in the process.

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“…At the same time, OxS promotes ER Stress. The ER is an organelle, abundant in hepatocytes, engaged in multiple functions, including lipid metabolism and calcium homeostasis [149]. Moreover, the ER is crucial, especially in the synthesis, folding, and modification of proteins [150].…”

Section: Liver and Oxidative Stressmentioning

confidence: 99%

Investigating the Link between Ketogenic Diet, NAFLD, Mitochondria, and Oxidative Stress: A Narrative Review

Paoli

Cerullo

2023

Antioxidants

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Together with the global rise in obesity and metabolic syndrome, the prevalence of individuals who suffer from nonalcoholic fatty liver disease (NAFLD) has risen dramatically. NAFLD is currently the most common chronic liver disease and includes a continuum of liver disorders from initial fat accumulation to nonalcoholic steatohepatitis (NASH), considered the more severe forms, which can evolve in, cirrhosis, and hepatocellular carcinoma. Common features of NAFLD includes altered lipid metabolism mainly linked to mitochondrial dysfunction, which, as a vicious cycle, aggravates oxidative stress and promotes inflammation and, as a consequence, the progressive death of hepatocytes and the severe form of NAFLD. A ketogenic diet (KD), i.e., a diet very low in carbohydrates (<30 g/die) that induces “physiological ketosis”, has been demonstrated to alleviate oxidative stress and restore mitochondrial function. Based on this, the aim of the present review is to analyze the body of evidence regarding the potential therapeutic role of KD in NAFLD, focusing on the interplay between mitochondria and the liver, the effects of ketosis on oxidative stress pathways, and the impact of KD on liver and mitochondrial function.

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Role of endoplasmic reticulum stress in hepatic glucose and lipid metabolism and therapeutic strategies for metabolic liver disease

Cited by 12 publications

References 128 publications

Nanoparticles alleviate non-alcoholic steatohepatitis via ER stress sensor-mediated intestinal barrier damage and gut dysbiosis

Nanoparticles alleviate non-alcoholic steatohepatitis via ER stress sensor-mediated intestinal barrier damage and gut dysbiosis

The Effects and Regulatory Mechanism of Casein-Derived Peptide VLPVPQK in Alleviating Insulin Resistance of HepG2 Cells

Investigating the Link between Ketogenic Diet, NAFLD, Mitochondria, and Oxidative Stress: A Narrative Review

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