Research Article Details

Article ID: A15966
PMID: 28635324
Source: Antioxid Redox Signal
Title: Gliptins Suppress Inflammatory Macrophage Activation to Mitigate Inflammation, Fibrosis, Oxidative Stress, and Vascular Dysfunction in Models of Nonalcoholic Steatohepatitis and Liver Fibrosis.
Abstract: AIMS: Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, panlobular inflammation, liver fibrosis, and increased cardiovascular mortality. Dipeptidyl peptidase-4 inhibitors (gliptins) are indirect glucagon-like peptide 1 agonists with antidiabetic and anti-inflammatory activity, used for the treatment of type 2 diabetes. Their potential and underlying mechanisms to treat metabolic liver inflammation and fibrosis as well as the associated vascular dysfunction remain to be explored. RESULTS: In the methionine/choline-deficient (MCD) diet and Mdr2-/- models of NASH and liver fibrosis, treatment with sitagliptin and linagliptin significantly decreased parameters of steatosis and inflammation, which was accompanied by suppression of hepatic transcript levels reflecting metabolic inflammation and fibrosis, including SREBP-1c, FAS, TNFα, iNOS, α-SMA, Col1α1, and MMP-12. Moreover, gliptins reduced the number of liver infiltrating CD11b+Ly6Chi proinflammatory monocytes/macrophages and liver-resident F4/80+ macrophages, with an increase of Ym1+ alternative macrophages and (anti-inflammatory) macrophage markers Arg1 and IL-10. This was paralleled by decreased hepatic and aortic reactive oxygen species (ROS) production and NOX-2 mRNA expression, a normalization of endothelial dysfunction, cardiac NADPH oxidase activity, mitochondrial ROS formation, and whole blood oxidative burst in the MCD model. Innovation and Conclusions: Gliptins via suppression of inflammation decrease steatosis, apoptosis, oxidative stress, and vascular dysfunction in murine models of NASH and liver fibrosis, with mild direct antifibrotic properties. They reduce the numbers of liver and vascular inflammatory monocytes/macrophages and induce their alternative polarization, with beneficial effect on NASH-associated hepatic and cardiovascular complications. Therefore, gliptins qualify as drugs for treatment of NASH and associated liver fibrosis and cardiovascular complications. Antioxid. Redox Signal. 28, 87-109.
DOI: 10.1089/ars.2016.6953

Strategy ID Therapy Strategy Synonyms Therapy Targets Therapy Drugs
S13 Anti-apoptosis hepatocyte apoptosis; hepatic autophagy; apoptosis Pan-caspase inhibitor Emricasan Details
S03 Anti-fibrosis fibrosis Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 Details
S04 Anti-oxidative stress oxidative stress α-tocopherol: antioxidant Vitamin E Details
S05 Anti-inflammatory inflammatory Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; Details

Target ID Target Name GENE Action Class UniProtKB ID Entry Name
T08 Tumor necrosis factor TNF inhibitor Cytokine P01375 TNFA_HUMAN Details
T10 Caspase-1 CASP1 inhibitor Enzyme P29466 CASP1_HUMAN Details
T18 Acetyl-CoA carboxylase 1 ACACA inhibitor Enzyme Q13085 ACACA_HUMAN Details
T20 Fatty acid synthase FASN inhibitor Enzyme P49327 FAS_HUMAN Details

Diseases ID DO ID Disease Name Definition Class
I05 9352 Type 2 diabetes mellitus A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus Details

Drug ID Drug Name Type DrugBank ID Targets Category Latest Progress
D579 Emfilermin Miscellany -- adipocytes Enhance lipid metabolism Under investigation Details
D075 Choline Supplement DB00122 PLD2 product of; PLD1 product of -- Under clinical trials Details
D205 Linagliptin Chemical drug DB08882 DPP4 inhibitor -- Under clinical trials Details
D338 Sitagliptin Chemical drug DB01261 DPP4 inhibitor Antidiabetic drug Under clinical trials Details
D155 Glucagon Biological drug DB00040 GCGR agonist Antidiabetic drug Under clinical trials Details