Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Jan 23;10(3):e25053.
doi: 10.1016/j.heliyon.2024.e25053. eCollection 2024 Feb 15.

Pharmacology of bioactive compounds from plant extracts for improving non-alcoholic fatty liver disease through endoplasmic reticulum stress modulation: A comprehensive review

Liying Huang  1   2 , Liping Tan  1   2 , Zhuo Lv  1   2 , Wenhui Chen  1   2 , Junzi Wu  1   2
Affiliations
Review

Pharmacology of bioactive compounds from plant extracts for improving non-alcoholic fatty liver disease through endoplasmic reticulum stress modulation: A comprehensive review

Liying Huang et al. Heliyon. .

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition with significant clinical implications. Emerging research indicates endoplasmic reticulum (ER) stress as a critical pathogenic factor governing inflammatory responses, lipid metabolism and insulin signal transduction in patients with NAFLD. ER stress-associated activation of multiple signal transduction pathways, including the unfolded protein response, disrupts lipid homeostasis and substantially contributes to NAFLD development and progression. Targeting ER stress for liver function enhancement presents an innovative therapeutic strategy. Notably, the natural bioactive compounds of plant extracts have shown potential for treating NAFLD by reducing the level of ER stress marker proteins and mitigating inflammation, stress responses, and de novo lipogenesis. However, owing to limited comprehensive reviews, the effectiveness and pharmacology of these bioactive compounds remain uncertain.

Objectives: To address the abovementioned challenges, the current review categorizes the bioactive compounds of plant extracts by chemical structures and properties into flavonoids, phenols, terpenoids, glycosides, lipids and quinones and examines their ameliorative potential for NAFLD under ER stress.

Methods: This review systematically analyses the literature on the interactions of bioactive compounds from plant extracts with molecular targets under ER stress, providing a holistic view of NAFLD therapy.

Results: Bioactive compounds from plant extracts may improve NAFLD by alleviating ER stress; reducing lipid synthesis, inflammation, oxidative stress and apoptosis and enhancing fatty acid metabolism. This provides a multifaceted approach for treating NAFLD.

Conclusion: This review underscores the role of ER stress in NAFLD and the potential of plant bioactive compounds in treating this condition. The molecular mechanisms by which plant bioactive compounds interact with their ER stress targets provide a basis for further exploration in NAFLD management.

Keywords: Bioactive compounds; Endoplasmic reticulum stress; Non-alcoholic fatty liver disease; Sterol-regulated cascade response; Unfolded protein reaction.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
UPR, SRCR and EOR interact with lipid metabolic pathways. (A) UPR signalling pathways. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) activates protein kinase B (AKT), promoting adipogenesis under ER stress. Simultaneously, PERK stimulates the expression of key adipogenic regulators CCAAT/enhancer binding protein α (C/EBPα), C/EBPβ and peroxisome proliferator-activated receptor γ (PPARγ) and reduces the protein translation of insulin-induced gene 1 (Insig1), thereby enhancing the activation of sterol regulatory element binding protein (SREBP) through the phosphorylation of eukaryotic initiation factor 2α (eIF2α). However, under conditions of severe or prolonged ER stress, the downstream expression of CHOP, regulated by activating transcription factor 4 (ATF4), may disrupt the balance of C/EBPs. In addition, the inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP1) pathway contributes to hepatic lipid accumulation by inducing an increase in the expression of lipogenic genes and augmenting C/EBPα activity. (B) SRCR pathway. Insig and SREBP/SREBP cleavage‐activating protein (SCAP) complex dissociates from the ER membrane during ER stress. Subsequently, the SREBP–SCAP complex translocates to the Golgi apparatus, where it undergoes proteolytic cleavage by site 1 and site 2 proteases. The cleaved SREBP fragment enters the nucleus and activates genes responsible for sterol and lipid biosynthesis and uptake. (C) EOR pathway. ER stress, induced by the accumulation of misfolded proteins, prompts the release of Ca2+ from the ER into the cytoplasm, inducing the generation of reactive oxygen intermediates (ROIs). Consequently, the EOR pathway is activated, leading to the nuclear translocation of hepatic nuclear factor-kappa B (NF-κB). This, in turn, contributes to insulin resistance (IR) and inflammation, which exerts an influence on lipid accumulation. In summary, Fig. 2 delineates the pivotal role of transcription factors, such as ATF4, XBP1s, ATF6, SREBP and NF-κB, in orchestrating lipid metabolism within the framework of UPR, SRCR and EOR pathways.
Fig. 2
Fig. 2
Cellular function of SRCR in lipidogenesis. Excessive accumulation of fatty acids (FAs) in NAFLD induces ER stress, which activates SRCR, resulting in the generation of phospholipid bilayers by the SREBP/SCAP complex. This augments TG content through the amplification of de novo lipogenesis (DNL). Furthermore, cleaved SREBP undergoes nuclear translocation, where it functions as a transcription factor, binding to sterol response elements (SREs). Notably, SREBP can directly enhance the transcription of genes pivotal for the synthesis and uptake of cholesterol, FA, TG and phospholipids. Despite governing distinct biosynthetic pathways, each isoform of SREBP operates under the regulatory influence of sterols and SCAP.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Lee E., Korf H., Vidal-Puig A. An adipocentric perspective on the development and progression of non-alcoholic fatty liver disease. J. Hepatol. 2023;78:1048–1062. doi: 10.1016/j.jhep.2023.01.024. - DOI - PubMed
    1. Röhrl C., Eigner K., Winter K., Korbelius M., Obrowsky S., Kratky D., Kovacs W.J., Stangl H. Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells. J. Lipid Res. 2014;55:94–103. doi: 10.1194/jlr.M043299. - DOI - PMC - PubMed
    1. Walter P., Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334:1081–1086. doi: 10.1126/science.1209038. - DOI - PubMed
    1. Puri P., Mirshahi F., Cheung O., Natarajan R., Maher J.W., Kellum J.M., Sanyal A.J. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology. 2008;134:568–576. doi: 10.1053/j.gastro.2007.10.039. - DOI - PubMed
    1. Pahl H.L., Baeuerle P.A. The ER-overload response: activation of NF-κB. Trends Biochem. Sci. 1997;22:63–67. doi: 10.1016/S0968-0004(96)10073-6. - DOI - PubMed

LinkOut - more resources