Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH), is the advanced stage of nonalcoholic fatty liver disease (NAFLD) with rapidly rising global prevalence. It is featured with severe hepatocyte apoptosis, inflammation and hepatic lipogenesis. The drugs directly targeting the processes of steatosis, inflammation and fibrosis are currently under clinical investigation. Nevertheless, the long-term ineffectiveness and remarkable adverse effects are well documented, and new concepts are required to tackle with the root causes of NASH progression. We critically assess the recently validated drug targets that regulate the systemic metabolism to ameliorate NASH. Thermogenesis promoted by mitochondrial uncouplers restores systemic energy expenditure. Furthermore, regulation of mitochondrial proteases and proteins that are pivotal for intracellular metabolic homeostasis normalize mitochondrial function. Secreted proteins also improve systemic metabolism, and NASH is ameliorated by agonizing receptors of secreted proteins with small molecules. We analyze the drug design, the advantages and shortcomings of these novel drug candidates. Meanwhile, the structural modification of current NASH therapeutics significantly increased their selectivity, efficacy and safety. Furthermore, the arising CRISPR-Cas9 screen strategy on liver organoids has enabled the identification of new genes that mediate lipid metabolism, which may serve as promising drug targets. In summary, this article discusses the in-depth novel mechanisms and the multidisciplinary approaches, and they provide new horizons to treat NASH.

Keywords: Drug discovery; Drug targets; Energy expenditure; Mechanisms; Metabolic homeostasis; NASH.

Fig. 1

Framework of the whole article and schematic illustration of the emerging drug targets and strategies that will be focused on in the article.

Fig. 2

Optimization of current NASH drugs increases potency and selectivity. Upper left: Optimized FXR agonists MET409 selectively stabilize conformation of FXR and activate FXR signaling transduction; Below left: TGR5 agonist with intestine-directing group (labeled with red) specifically targets TGR5 in intestine and alleviates metabolic complications; Upper right: Optimization of PPARα/δ agonist GFT505 lowers toxicity and metabolic complications (The optimized moieties are labeled with red); Below right: Optimization of THRβ receptor agonists increases the selectivity, lowers the cardiotoxicity and enhances the potencies. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Normalization of systemic metabolism resolves NASH. (A) Targeting the key pathways in systemic metabolism during NASH progression, e.g. GLP-1 and aldolase effectively ameliorate NASH in rodents and human subjects; (B) Dysfunction of mitochondria leads to aberrant accumulation of lipids and ROS. They trigger dysregulation in whole body metabolic homeostasis, metabolic disorders and NASH. (C) Elevation of thermogenesis in mitochondria with mitochondrial uncouplers by activating both UCP1 and AAC increases energy expenditure and alleviates NASH by normalization of systemic metabolism.

Fig. 4

Illustration of novel genes that regulate mitochondrial function, NASH progression and their small molecular modulators. (A) The recently identified genes modulate mitochondrial function and thus NASH progression. (B) A54556A activates ClpP and results in normalization of mitochondrial protein homeostasis to resolve NASH; (C) MRG-15 interacts with LRH-1 in nucleus and triggers the transcription of lipogenic genes, which is blocked by Argatroban. Acetylation of MRG-15 by inflammatory factors promotes the ubiquitination (Ub) of TUFM and its degradation by ClpP; (D) The overview of DDX's function in blocking NASH progression. DDX5 interacts with E2F1 to stimulate the transcription of Atg4B and leads to mitophagy. Hyperforcinol K inhibits the ubiquitination of DDX and thereby inactivating mTORC1 signaling pathways to suppress NASH progression.

Fig. 5

Novel drug targets that significantly regulate NASH progression. (A) IRE1α inhibitorsblock ER stress to alleviate NASH progression; (B) Highly potent HSD17B13 inhibitors block the function of HSD17B13, which is freely available via the opnMe platform; (C) Dyrk1b inhibitors suppress mTORC2 function and thus lipogenesis, as well as increase incretin-expressing cells in intestine.

Fig. 6

Secreted proteins from multiple organs regulate the progression of NASH and the therapeutics that target the signaling transduction to resolve NASH. (A) Overview of representative secreted proteins which are recently validated to resolve NASH; (B) Adiponectin receptor agonists JT003 (peptide), AdipoRon and optimized derivative Q7 bind to and activate adipoR1 and adipoR2 simultaneously to resolve NASH; (C) Mechanism of RBP4 in vivo and blockade of its signaling transduction by its antagonist BPN-14136. RBP4 antagonists STG-001 and tinlarebant are currently in clinical trials.