Korean J Physiol Pharmacol.  2023 Jul;27(4):299-310. 10.4196/kjpp.2023.27.4.299.

Experimental model and novel therapeutic targets for non-alcoholic fatty liver disease development

• Jin Y
• Heo KS

• KMID: 2544132
• DOI: http://doi.org/10.4196/kjpp.2023.27.4.299

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a complex disorder characterized by the accumulation of fat in the liver in the absence of excessive alcohol consumption. It is one of the most common liver diseases worldwide, affecting approximately 25% of the global population. It is closely associated with obesity, type 2 diabetes, and metabolic syndrome. Moreover, NAFLD can progress to non-alcoholic steatohepatitis, which can cause liver cirrhosis, liver failure, and hepatocellular carcinoma. Currently, there are no approved drugs for the treatment of NAFLD. Therefore, the development of effective drugs is essential for NAFLD treatment. In this article, we discuss the experimental models and novel therapeutic targets for NAFLD. Additionally, we propose new strategies for the development of drugs for NAFLD.

Keyword

Drug targeting; Hepatitis; Metabolic syndrome; Non-alcoholic fatty liver disease

Figure

• 

  Fig. 1 Pathogenesis of non-alcoholic fatty liver disease (NAFLD) progression. Various factors including hyperglycemia, hyperlipidemia, and insulin resistance signaling pathways are involved in the NAFL and NASH progression by accelerating the inflammatory signaling pathway and its mediated apoptosis. Additionally, continuous activities NAFLD involved into accumulating of liver fibrosis and genetic exchange. Finally, hepatocarcinoma was activated and patients need to surgical treatment. NAFL, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis.

• 

  Fig. 2 Mechanisms of inflammation on NAFLD progression. (A) TNF-α or LPS activates each receptor, such as TNFR and LPS4 or 9, leading to increase NF-κB phosphorylation through the activation of MAPK, STAT3, JNK, or AMPK expression. Additionally, the production of reactive oxygen species (ROS) contributes to mitochondrial dysfunction and inflammasome activation, which in turn accelerate IL-1β maturation and secretion. (B) miR-34a inhibited MAPK-mediated NF-κB phosphorylation via activation of TLR4, which is triggered by LPS or high-glucose levels. Besides, NF-κB-mediated TNF-α induction activates its receptor and activated inflammatory signaling pathway. However, this signaling pathway is inactivated by miR-125b/TRNAIP3-mediated TNF-α receptor ubiquitination. In addition, IL-6 secretion by NF-κB activation increased phosphorylation of STAT3 and activated miR-233-enriched exosome which was source of IL-6 over production. Accelerated inflammatory signaling pathway induced PERK-mediated eIF2α phosphorylation suppressed by miR-26a and miR-26a suppressed eIF2α-activated NF-κB p65 translocation into nucleus. Moreover, high-glucose activated IRS-1/AKT signaling pathway and FOXO3 that suppressed by miR-122-5p activation. (C) The environment of the intestine and liver is closely linked to the disruption of gut microbiota, which can be induced by dysregulation of diets. Briefly, LPS secreted by disruption of gut microbiota increased gut inflammation through inactivating AMPK/PPARβ/δ mechanisms. Moreover, dephosphorylation of AMPK-mediated PPARα suppression caused by disruption of gut microbiota increased PGC1α-mediated lipid metabolisms and induced liver steatosis. In addition, activation of PPARγ stabilized cellular homeostasis through induction of IL-10 and iNOS mRNA expression. Furthermore, LPS comes from dysfunction of gut microbiota activated TLR4-mediated NF-κB signaling pathway in hepatocyte through blood flow in portal vein. NAFLD, non-alcoholic fatty liver disease; TNF-α, tumor necrosis factor-α; NF-κB, nuclear factor of kappa photopolypeptide enhancer; MAPK, mitogen-activated protein kinase; STAT3, signal transducer and activator of transcription 3; AMPK, AMP-activated protein kinase; IL, interleukin; TLR, toll-like receptor; IRS-1, insulin receptor substrate 1; PPAR, peroxisome proliferator-activated receptor; PGC1α, PPARγ coactivator-1α; iNOS, inducible nitric oxide synthase; ER, endoplasmic reticulum; HFD, high-fat diet; FFA, free fatty acid.

• 

  Fig. 3 Mechanisms of apoptosis in NAFLD patient. Liver apoptosis plays several roles in NAFLD progression. Factors such as high glucose levels or cellular dysfunction, including reactive oxygen species (ROS) production, ROS-mediated mitochondrial dysfunction, and endoplasmic reticulum (ER) stress signaling pathways, contribute to the expression of Bax. Mechanistically, PERK-mediated CHOP expression induced Bax mRNA expression, which is one of inducers on mitochondrial dysfunction-mediated apoptosis signaling pathway. After mitochondrial dysfunction occurs cytochrome C releasement required caspase-3 and cleaved PARP ex-pression. In addition, damaged mitochondria produce mtROS and mtROS activated STING/IRF3 phosphorylation-mediated BAX mRNA expression. In addition, complex with SRSF6 and DRAK2 induced abnormal mRNA production of Polg2, Rnasel, and Nme4 and its abnormal form induced mitochondrial dysfunction-mediated hepatocyte apoptosis. Moreover, AMPK activation sup-pressed cleaved caspase-6-mediated apoptosis signaling pathway. NAFLD, non-alcoholic fatty liver disease; CHOP, c/EBP homologous protein; mtROS, mitochondrial ROS; STING, stimulator of interferon gene; IRF3, interferon regulatory factor 3; AMPK, AMP-activated protein kinase.

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