A GLP‐1/GLP‐2 receptor dual agonist to treat NASH: Targeting the gut‐liver axis and microbiome

Abstract

Background and Aims Currently there is no Food and Drug Administration–approved drug to treat NAFLD and NASH, the rates of which are increasing worldwide. Although NAFLD/NASH are highly complex and heterogeneous conditions, most pharmacotherapy pipelines focus on a single mechanistic target. Considering the importance of the gut‐liver axis in their pathogenesis, we investigated the therapeutic effect of a long‐acting dual agonist of glucagon‐like peptide (GLP)‐1 and GLP‐2 receptors in mice with NAFLD/NASH. Approach and Results C57BL/6J mice were fed a choline‐deficient high‐fat diet/high fructose and sucrose solution. After 16 weeks, mice were randomly allocated to receive vehicle, GLP1‐Fc, GLP2‐Fc, or GLP1/2‐Fc fusion (GLP1/2‐Fc) subcutaneously every 2 days for 4 weeks. Body weight was monitored, insulin/glucose tolerance tests were performed, feces were collected, and microbiome profiles were analyzed. Immobilized cell systems were used to evaluate direct peptide effect. Immunohistochemistry, quantitative PCR, immunoblot analysis, tunnel assay, and biochemical assays were performed to assess drug effects on inflammation, hepatic fibrosis, cell death, and intestinal structures. The mice had well‐developed NASH phenotypes. GLP1/2‐Fc reduced body weight, glucose levels, hepatic triglyceride levels, and cellular apoptosis. It improved liver fibrosis, insulin sensitivity, and intestinal tight junctions, and increased microvillus height, crypt depth, and goblet cells of intestine compared with a vehicle group. Similar effects of GLP1/2‐Fc were found in in vitro cell systems. GLP1/2‐Fc also changed microbiome profiles. We applied fecal microbiota transplantation (FMT) gain further insight into the mechanism of GLP1/2‐Fc–mediated protection. We confirmed that FMT exerted an additive effect on GLP1‐Fc group, including the body weight change, liver weight, hepatic fat accumulation, inflammation, and hepatic fibrosis. Conclusions A long‐acting dual agonist of GLP‐1 and GLP‐2 receptors is a promising therapeutic strategy to treat NAFLD/NASH.

Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

“…↓Liver fibrosis, insulin sensitivity. 608 GCGR and GLP-1R dual agonist Oxyntomodulin (OXM) analog Diabetogenic diet-induced obese (DIO) mouse model ↓Liver lipid content ↓Fat mass 609 Lipid metabolism ACC inhibitor ND-630 HFD or HSD diet-rat model ↓Hepatic steatosis ↑Insulin sensitivity ↓Weight gain 610 ND-654 Diethylnitrosamine (DEN) induced HCC rat model ↓Hepatic DNL ↓Development of HCC 611 WZ66 HFD-diet mouse model ↓Seatosis ↓KCs and HSCs activation ↓Hepatic TGs and other lipids including diglycerides (DGs), phosphatidylcholine (PC), and sphingomyelin (SM) ↓ Allobaculum , Mucispirillum , and Prevotella genera as well as Mucispirillum schaedleri species in gut microbiota. 612 ALOX12-ACC inhibitor IMA-1 High-fat/high-cholesterol (HFHC) diet-induced NASH mouse model HFHC diet-induced NASH Cynomolgus macaque model ↓NASH progression 613 Lipid metabolism Hepatic stimulator substance (HSS) Overexpression of HSS HFD or MCD diet-fed HSS gene-transfected mouse mode ↓Hepatic steatosis ↓Hepatic inflammation ↑Activity of CPT-1 614 ACLY inhibitor Hydroxy citrate HFD-fed rat model ↓ALT, AST ↓GGT, LDH 82 Bempedoic acid (ETC-1002) HFD-fed mouse model ↓Body weight ↑Glycemic control ↓Hepatic TG and TC ↓Inflammatory, fibrosis ↓NAS score 79 Lipid metabolism SREBP inhibitor 25-HL Western-type diet (WD)-fed mouse model Amylin liver NASH model (AMLN) diet-fed Ldlr −/− male mice mouse model ↑Energy expenditure ↓TC and TG in serum and liver ↓Hepa...…”

Pyocyanin Modulates Gastrointestinal Transformation and Microbiota

“…Serum FITC-d levels were determined by an Infinite M200 Microplate reader (Tecan), with the excitation wavelength of 485 nm and the emission wavelength of 535 nm. 20 Liver Metabolomics. For metabolomic analysis, the murine liver was homogenized by a tissue lyser (Qiagen, Germany).…”

Circadian secretion rhythm of GLP-1 and its influencing factors

“…Furthermore, GLP-1 analogs, such as liraglutide, dulaglutide, and semaglutide, are now widely used in the clinic to treat patients with diabetes and obesity by various mechanisms, including anti-inflammation, emergency improvement, intestinal flora regulation, appetite suppression via the central nervous system, and weight reduction (121)(122)(123). Exogenous GLP-1 analog supplementation can restore the GLP-1 physiological secretion rhythm and the circadian rhythm of islet function (117,124), which might be closely related to the aforementioned metabolic benefits when exogenously supplementing GLP-1 analogs.…”