title: Linagliptin alleviates fatty liver disease in diabeticdb/dbmice.
abstract: OBJECTIVE
  To study the effects of linagliptin on the structural signs of non-alcoholic fatty liver disease (NAFLD) indb/dbmice.
  
  
  METHODS
  Male diabeticdb/dbmice (BKS.Cg-Dock7m+/+Leprdb/J) aged 10 wk received the dipeptidyl peptidase 4 (DPP4) inhibitor linagliptin (10 mg/kg) or saline as a placebo once per day by gavage for 8 wk. Intactdb/dbmice served as controls. Structural changes in the liver were analyzed from light and electron microscopic images of sections from intact, placebo-treated and linagliptin-treated animals. We estimated the changes in hepatocytes, sinusoidal cells, liver microvasculature and lymphatic roots. Hepatic staining for lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) was assessed by immunohistochemistry.
  
  
  RESULTS
  In 18-wk-old diabetic mice, liver steatosis (predominantly microvesicular and mediovesicular steatosis) was accompanied by dilation of the roots of the lymphatic system, interlobular blood vessels and bile canaliculi. Compared to saline-treated mice, linagliptin-treated mice exhibited a reduction in the mean numeral densities of hepatocytes with lipid droplets (92.4% ± 1.7%vs64.9% ± 5.8% per field of view,P= 0.0002) and a lower proportion of hepatocytes with a high density of lipid droplets (20.7% ± 3.6%vs50.4% ± 3.1%,P= 0.0007). We observed heterogeneous hepatocytes and relatively preserved cell structures in the linagliptin group. Dilation of blood and lymphatic vessels, as well as ultrastructural changes in the hepatocyte endoplasmic reticulum and mitochondria, were alleviated by linagliptin treatment. In intact and placebo-treated mice, immunohistochemical staining for LYVE-1 was observed in the endothelial cells of interlobular lymphatic vessels and on the membranes of some endothelial sinusoidal cells. We observed an enlarged LYVE-1 reaction area in linagliptin-treated mice compared to intact and placebo-treated mice. The improvement in the structural parameters of the liver in linagliptin-treated mice was independent to changes in the plasma glucose levels.
  
  
  CONCLUSIONS
  The DPP4 inhibitor linagliptin alleviates liver steatosis and structural changes in the hepatic microvasculature and lymphatic roots in a model of NAFLD in diabeticdb/dbmice.
authors.affiliation: Svetlana V Michurina, Irina Ju Ishenko, Sergey A Archipov, Laboratory of Functional Morphology, Scientific Institute of Clinical and Experimental Lymphology, 630060 Novosibirsk, Russia.
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Michurina
authors.affiliation: Svetlana V Michurina, Irina Ju Ishenko, Sergey A Archipov, Laboratory of Functional Morphology, Scientific Institute of Clinical and Experimental Lymphology, 630060 Novosibirsk, Russia.
authors.forename: Irina Ju
authors.initials: IJ
authors.lastname: Ishenko
authors.affiliation: Svetlana V Michurina, Irina Ju Ishenko, Sergey A Archipov, Laboratory of Functional Morphology, Scientific Institute of Clinical and Experimental Lymphology, 630060 Novosibirsk, Russia.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Klimontov
authors.affiliation: Svetlana V Michurina, Irina Ju Ishenko, Sergey A Archipov, Laboratory of Functional Morphology, Scientific Institute of Clinical and Experimental Lymphology, 630060 Novosibirsk, Russia.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Archipov
authors.affiliation: Svetlana V Michurina, Irina Ju Ishenko, Sergey A Archipov, Laboratory of Functional Morphology, Scientific Institute of Clinical and Experimental Lymphology, 630060 Novosibirsk, Russia.
authors.forename: Natalia E
authors.initials: NE
authors.lastname: Myakina
authors.affiliation: Svetlana V Michurina, Irina Ju Ishenko, Sergey A Archipov, Laboratory of Functional Morphology, Scientific Institute of Clinical and Experimental Lymphology, 630060 Novosibirsk, Russia.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Cherepanova
authors.affiliation: Svetlana V Michurina, Irina Ju Ishenko, Sergey A Archipov, Laboratory of Functional Morphology, Scientific Institute of Clinical and Experimental Lymphology, 630060 Novosibirsk, Russia.
authors.forename: Eugenii L
authors.initials: EL
authors.lastname: Zavjalov
authors.affiliation: Svetlana V Michurina, Irina Ju Ishenko, Sergey A Archipov, Laboratory of Functional Morphology, Scientific Institute of Clinical and Experimental Lymphology, 630060 Novosibirsk, Russia.
authors.forename: Galina V
authors.initials: GV
authors.lastname: Koncevaya
authors.affiliation: Svetlana V Michurina, Irina Ju Ishenko, Sergey A Archipov, Laboratory of Functional Morphology, Scientific Institute of Clinical and Experimental Lymphology, 630060 Novosibirsk, Russia.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Konenkov
keywords: Diabetes; Dipeptidyl peptidase 4; Linagliptin; Non-alcoholic fatty liver disease; Obesity