Recent advances of hepatoprotective peptides

Introduction

Peptides are short, variable-length amino acid (AA) chains connected by peptide bonds. They are considered as effective AA sources owing to their higher in vivo absorption than AA monomers. These compounds have demonstrated efficacy in treating a range of lifestyle-related illnesses, such as alcoholic and non-alcoholic liver disease, hypercholesterolemia, atherosclerosis, etc. (Cho & Lee, 2020). Lately, there has been a surge in research into food-derived bioactive peptides. Various peptides from animal and plant origin (such as milk (Sansi et al., 2023), egg (Zheng, et al., 2020), fish (Ortizo, et al., 2023), meat (Mora, et al., 2020), soybean (Li, et al., 2021), and cereals (Chan-Zapata, et al., 2022)) have been exploited for their bioactive peptides, revealing diversified biological activities.

The liver is a vital organ with the primary function in metabolism and detoxification (Lv, et al., 2013). Excessive alcohol intake is the leading cause of liver-related death. Alcoholic hepatitis is a neuroinflammatory response associated with rapid fibrosis progression, in which 20% of cases develop into cirrhosis (Dukić, et al., 2023). A consensus describes the mechanism of ethanol-induced liver damage involves lipid buildup in hepatocytes, which results in cell death by oxidative stress after cell damage. Non-alcoholic fatty liver disease (NAFLD) is the major trigger for cirrhosis and hepatocellular cancer. Cardiovascular and extrahepatic malignancy are the primary causes of death in persons with NAFLD, with severe liver fibrosis being a critical prognostic marker for liver-related outcomes and total mortality (Powell, et al., 2021). Chemotherapy uses corticosteroids, antiviral drugs, and immunosuppressants to treat the liver, causing serious side effects and even liver damage after long-term administration (Siregar, et al., 2021).

The intestine and liver are intimately linked and interact through the portal vein and the biliary system. As the knowledge regarding the gut-liver axis has improved in the last decade, the interplay between bioactive peptides and gut microbiota (GM) is extensively studied. Liver diseases have been positively related to dysbiosis of GM, which impairs gut barrier integrity, implying that targeting GM and restoring gut barrier function might be a future treatment method (Wahlstrom, 2019). More recently, compelling evidence has been made in ameliorating liver ailments using peptides through GM regulation (Ding, et al., 2023). However, the interaction of peptides with microbiota still needs to be researched.

Peptides with hepatoprotective potency can play a vital role against liver diseases due to their high antioxidant activity and efficiency. Smaller peptides display more significant antioxidant activity and inhibited lipid peroxidation in comparison to larger chain peptides (Ren, et al., 2021). Cai et al. (2015)) discovered that short-chain peptides with molecular weights (MW) ranging from 480 to 640 Da showed robust free radical-scavenging activity. In addition, other researchers found that peptides composed of hydrophobic AA residues, such as Leu, Asp, Ser, Glu, and Lys, possessed highly potent antioxidants (Ben Hamad Bouhamed & Kechaou, 2017).

Bioactive peptides with specific attributes have been used to combat various diseases. Some review papers have been published focusing on the “Bioactive peptides from food fermentation: A comprehensive review of their sources, bioactivities, applications, and future development” (Chai, et al., 2020) and “Bioactive peptides and gut microbiota: Candidates for a novel strategy for reduction and control of neurodegenerative diseases”(Wu, et al., 2021). However, no review is available regarding the impact of peptides on liver disease, specifically the interactions between hepatoprotective peptides and intestinal microbiota. This review delivers a summary of the sources, manufacturing, structure, and sequence of hepatoprotective peptides (Table 1). In addition, functional mechanisms of hepatoprotective peptides are illustrated in different liver illnesses, including alcoholic and non-alcoholic liver diseases. Furthermore, the interactions between hepatoprotective peptides and intestinal microbiota are also comprehensively summarized.

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Section snippets

Source of hepatoprotective peptides

In recent years, many bioactive peptides derived from different origins have shown hepatoprotective potential based on various in vitro and in vivo models (Shi, et al., 2021). They have been classified into four types by source: endogenous, marine organism, animals and plants (Fig. 1).

Mechanisms of hepatoprotective peptides on liver

Excess ROS generation causes oxidative stress, a major contributing factor to the pathogenesis of liver diseases (Fig. 3) (Leung & Nieto, 2013). Peptides antioxidant effect is primarily represented by their ability to scavenge free radicals (Panchal, et al., 2020), inhibit lipid peroxidation (Carrillo, et al., 2016), and chelate metals (Canabady-Rochelle, et al., 2018). Hepatoprotective peptides reduce the severity of liver injury, which includes cell necrosis and hepatic lesions. Ao and Li

Intestinal absorption pathway

Peptides generated in the intestinal lumen are transported across the epithelial cell monolayer into the bloodstream through the following manners: passive transcellular diffusion, transcytosis, paracellular transport, and carrier-mediated permeation (Fig. 4A).

PepT1 is capable of transporting a variety of short bioactive peptides, however it is only able to transfer di- and tripeptides, not tetra- or longer peptides. PepT1 is an active route that prioritizes recognizing peptides with shorter

Summary and prospect

As a safe and effective strategy for the prevention and treatment of liver diseases, bioactive peptides have attracted much attention in past ten years. Especially in the study of ALD and NAFLD, bioactive peptides have shown the important role of scavenging free radicals, improving antioxidant activity in vivo, and regulating key signalling pathways such as MAPK. The mechanism of hepatoprotective peptides acting on the liver through intestinal microbiota has also been gradually explored,

Funding source

The present research was supported by Zhejiang Provincial Natural Science Foundation of China (No. LQ23C200011) and China Postdoctoral Science Foundation (No. 2022M721715).

CRediT authorship contribution statement

Hao Zhong: Writing – review & editing, Writing – original draft, Methodology, Investigation, Conceptualization. Yuanyuan Jin: Writing – review & editing. Abdullah: Writing – review & editing, Writing – review & editing. Muhammad Hussain: Writing – review & editing. Xiaofeng Liu: Writing – review & editing. Fengqin Feng: Writing – review & editing. Rongfa Guan: Supervision, Funding acquisition, Conceptualization.

Declaration of competing interest

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.

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