The pathogenesis of metabolic associated steatohepatitis (MASH, formerly known as NASH) is complex, leading to a relatively large number of drug development targets, which primarily revolve around the regulation of energy metabolism, glucose metabolism, bile acid metabolism, inflammation, and fibrosis. Among these, targets related to the regulation of glucose and lipid metabolism include peroxisome proliferator-activated receptor (PPAR), acetyl-CoA carboxylase (ACC), glucagon-like peptide-1 (GLP-1), and thyroid hormone receptor (THR). Targets associated with the regulation of bile acid metabolism encompass farnesoid X receptor (FXR) and fibroblast growth factor receptor 19/21 (FGF19/21). Regarding targets involved in the inflammatory response, they comprise apoptosis signal-regulating kinase-1 (ASK1) and C-C chemokine receptor types 2 and 5 (CCR2/5).
1. Drug Therapeutic Targets for MASH Based on Glucose and Lipid Metabolism Regulation
① Peroxisome Proliferator-Activated Receptors (PPARs)
PPARs are a class of ligand-activated receptors belonging to the nuclear hormone receptor family. Three subtypes, PPARα, PPARδ, and PPARγ, have been identified in various species. They control numerous intracellular metabolic processes in the body and are classified as ligand-induced nuclear receptors. Upon binding with their respective ligands, PPARs become activated and subsequently bind with retinoid X receptors (RXRs) to form heterodimers. These PPARγ/RXR heterodimers then bind to PPAR response elements upstream of target gene promoters, ultimately regulating the transcription of these target genes. The interaction between the receptors and ligands elicits biological effects through the modulation of target gene expression. PPARs play crucial roles in regulating fatty acid metabolism, inflammatory responses, apoptosis, smooth muscle cell migration and proliferation, atherosclerosis, insulin resistance, glucose metabolism, and obesity. By participating in the development and progression of MASH through the regulation of signaling pathways such as the mitogen-activated protein kinase pathway, mitochondrial β-oxidation pathway, and nuclear factor-κB pathway, PPARs have emerged as important targets for the development of therapeutic drugs for MASH.
② Acetyl-CoA Carboxylase (ACC)
ACC is a biotin-containing enzyme that catalyzes the ATP-dependent carboxylation of acetyl-CoA to produce malonyl-CoA, a process closely related to fatty acid synthesis and metabolism. In mammals, there are two isoforms of ACC: ACC1, primarily located in the cytoplasm of adipogenic tissues such as the liver and adipose tissue, controls the biotin carboxylase reaction in the de novo lipogenesis (DNL) pathway of fatty acid synthesis. ACC2, on the other hand, is mainly found in the mitochondria of oxidative tissues like skeletal muscle, where it catalyzes the formation of malonyl-CoA. Malonyl-CoA acts as a potent allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT1), mediating the transport of fatty acids into mitochondria for oxidation. Studies have shown that ACC2 knockout mice exhibit higher rates of fatty acid oxidation and reduced fat accumulation when fed a high-fat or high-fat/high-carbohydrate diet. Compared to wild-type mice, ACC2 knockout mice have lower levels of non-esterified fatty acids and triglycerides in their blood, and display improved metabolic syndrome, indicating that ACC2 can prevent diet-induced obesity, maintain whole-body and hepatic insulin sensitivity, and prevent the development of fatty liver disease. By playing a pivotal role in both de novo fatty acid synthesis and fatty acid β-oxidation, inhibiting ACC enzyme activity can potentially treat MASH by reducing hepatic fat synthesis and enhancing fatty acid oxidation.
③ Glucagon-like peptide-1 (GLP-1)
GLP-1 is an incretin hormone crucial for glycemic control and weight regulation, secreted by intestinal L-cells. It stimulates insulin secretion through a glucose-dependent mechanism. GLP-1 is involved in regulating multiple metabolic pathways, encompassing the modulation of insulin secretion in response to glucose concentration changes, retardation of gastric emptying, and suppression of food intake. Furthermore, GLP-1 exhibits anti-inflammatory and anti-apoptotic effects, effectively lowering blood glucose by inducing insulin secretion and suppressing glucagon secretion. GLP-1 analogues have been shown to mitigate hepatic steatosis and insulin resistance in mouse models of fatty liver disease, while also enhancing glycemic control and reducing body weight among patients with type 2 diabetes. Notably, type 2 diabetes is a significant risk factor for the development of metabolic-associated fatty liver disease (MAFLD, previously known as MASH), and insulin resistance in the liver and adipose tissue has emerged as a pivotal driver of MAFLD's morbidity and mortality. Consequently, GLP-1 presents itself as an exceptionally appealing molecular target for MAFLD therapy.
④ Thyroid Hormone Receptor (THR)
Thyroid hormones serve as vital regulators of metabolic activities in mammals, and their effects are mediated through the activation of thyroid hormone receptors (THRs). THRs exist in two main subtypes: THRα and THRβ. THRα is predominantly distributed in the brain and heart tissues, whereas THRβ is highly expressed in hepatocytes. Animal studies have demonstrated that THRβ plays a crucial role in reducing triglyceride and cholesterol levels in the liver, promoting hepatocyte regeneration, enhancing insulin sensitivity, and inhibiting cellular apoptosis. Notably, the expression of THRβ is significantly reduced in the livers of patients with metabolic-associated steatohepatitis (MASH, formerly known as MASH). This reduction is attributed to THRβ's ability to lower blood lipids, influencing metabolic processes by modulating low-density lipoprotein cholesterol, serum triglycerides, and other metabolic factors. These changes contribute to the reduction of liver fat content and liver fat toxicity in MASH patients. Oral administration of THRβ agonists to diet-induced obese mouse models with advanced MASH and fibrosis has been shown to significantly decrease liver weight, hepatic steatosis, and liver fibrosis. Thus, THRβ receptors play a pivotal role in maintaining normal liver function.
2.Drug Therapeutic Targets for MASH Based on Bile Acid Metabolism Regulation
① Farnesoid X Receptor (FXR)
FXR belongs to the family of ligand-activated transcription factor nuclear receptors, characterized by a typical nuclear receptor structure. It is expressed in various organs and tissues but highly expressed in the liver and small intestine, with bile acids serving as its natural ligands. Upon activation, FXR regulates the expression of genes such as fibroblast growth factor 19, thereby reducing hepatic fat production and gluconeogenesis, eliminating very low-density lipoprotein, and improving insulin resistance. Additionally, FXR modulates metabolic pathways related to bile acid synthesis, lipid metabolism, glucose metabolism, inflammation, and fibrosis. In patients with metabolic-associated steatohepatitis (MASH), the expression level of FXR in the liver exhibits a negative correlation with disease severity. Studies have revealed that activating FXR can reverse insulin resistance and alleviate lipid metabolism abnormalities in obese Zucker rat models. Consequently, FXR has gradually emerged as a therapeutic target for MASH.
targeted drugs aimed at THRβ have yielded promising results in clinical trials for the treatment of MASH.
② Fibroblast growth factor receptor 19/21 (FGF19/21)
FGF19/21 ligands are intestinal hormones expressed in ileal epithelial cells. They require co-receptors to bind with FGF receptors for signal transduction, playing a pivotal role in regulating bile acid metabolism. This regulation encompasses controlling bile acid synthesis, lipogenesis, and energy homeostasis. FGF19 functions as an endocrine gastrointestinal hormone, inhibiting cholesterol-derived bile acid synthesis via cytochrome P450 7A1 and suppressing insulin-induced hepatic lipogenesis. Meanwhile, FGF21, highly expressed in the liver, counteracts hyperglycemia, elevated free fatty acids, and low amino acid supply, maintaining homeostasis by regulating energy, glucose, and lipid metabolism in the central nervous system and adipose tissue.
FGF19/21 analogs have shown potential in reducing hepatic steatosis in various mouse models of metabolic associated fatty liver disease (MAFLD), attracting the attention of MAFLD drug developers. Drugs developed based on FGF19/21 can facilitate weight loss and reduce steatosis in patients with obesity and type 2 diabetes. While FGF19/21 exhibits hypoglycemic effects in experimental animals, it fails to improve blood glucose levels in humans. However, concerns over safety issues, such as increased low-density lipoprotein cholesterol and blood pressure, limit the use of monotherapy targeting this receptor for MAFLD.
3.Anti-inflammatory Therapeutic Targets for MAFLD (Metabolic Associated Fatty Liver Disease)
① Apoptosis Signal-Regulating Kinase 1 (ASK1)
ASK1 is a member of the mitogen-activated protein kinase (MAPK) family of kinases that regulates apoptosis signaling. It governs crucial signaling pathways involving c-Jun N-terminal kinase (JNK) and p38 MAPK. Additionally, ASK1 serves as a pivotal molecule in inflammatory signaling pathways, with its pathway abnormally activated in the livers of obese individuals and patients with MAFLD. ASK1 promotes the regulation of lipid and glucose metabolism while driving inflammatory responses in the liver. Inhibition of ASK1 activity has shown to ameliorate the progression of MAFLD. Numerous studies have demonstrated that inhibiting ASK1 can improve inflammation and fibrosis in animal models of MAFLD, making it an attractive therapeutic target for this condition. However, evidence also suggests that some cancers are intimately linked to the cascades mediated by ASK1. Therefore, clinical trials targeting ASK1 for MAFLD treatment should thoroughly consider its potential impact on tumorigenesis.
② C-C Chemokine Receptor Types 2 and 5 (CCR2/5)
CCR2/5 and their respective ligands, C-C chemokine motif ligand 2 (CCL2) and C-C chemokine motif ligand 5 (CCL5), play crucial roles in recruiting inflammatory cells to the liver and activating hepatic stellate cells. Macrophage-mediated inflammatory responses and hepatic stellate cell activation are key drivers of progression across multiple stages of MAFLD (Metabolic Associated Fatty Liver Disease). Studies have demonstrated that CCR2/5 knockout or pharmacological inhibition of CCR2/5 results in reduced immune cell activation and decreased liver fibrosis in mice. CCR2/5 antagonists can improve fibrosis by reducing monocyte infiltration and altering hepatic macrophage subsets. Furthermore, CCR2/5 antagonists have been proven effective in reducing liver fibrosis in animal models of MAFLD. Consequently, CCR2/5 represents one of the therapeutic targets for MAFLD drug development. However, a limitation of targeting CCR2/5 in MAFLD treatment is its potential impact on upstream metabolic mechanisms that may contribute to fibrosis progression. Therefore, CCR2/5 antagonists may need to be combined with drugs targeting related pathways to improve steatosis.
References
[1] Li Guochao, Yu Man, Li Xiaofei, et al. Progress in Therapeutic Targets and Targeted Drug Development for Nonalcoholic Steatohepatitis [J]. Hebei Journal of Industrial Science and Technology, 2023, 40(03): 225-234.
[2] Xu Kun, Zhang Xu, Li Ying, et al. Advances in New Drug Research for Nonalcoholic Fatty Liver Disease [J]. Journal of Clinical Hepatology, 2021, 37(07): 1699-1703.
About the Author
Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.
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