Circulating dipeptidyl peptidase‐4 activity correlates with measures of hepatocyte apoptosis and fibrosis in non‐alcoholic fatty liver disease in type 2 diabetes mellitus and obesity: A dual cohort cross‐sectional study

Liver fibrosis is a progressive pathological process involving inflammation and extracellular matrix deposition. Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a cell surface glycoprotein and serine protease. DPP4 binds to fibronectin, can inactivate specific chemokines, incretin hormone and neuropeptides, and influences cell adhesion and migration. Such properties suggest a pro-fibrotic role for this peptidase but this hypothesis needs in vivo examination. Experimental liver injury was induced with carbon tetrachloride (CCl) in DPP4 gene knockout (gko) mice. DPP4 gko had less liver fibrosis and inflammation and fewer B cell clusters than wild type mice in the fibrosis model. DPP4 inhibitor-treated mice also developed less liver fibrosis. DNA microarray and PCR showed that many immunoglobulin (Ig) genes and some metabolism-associated transcripts were differentially expressed in the gko strain compared with wild type. CCl-treated DPP4 gko livers had more IgM and IgG intrahepatic lymphocytes, and fewer CD4, IgD and CD21 intrahepatic lymphocytes. These data suggest that DPP4 is pro-fibrotic in CCl-induced liver fibrosis and that the mechanisms of DPP4 pro-fibrotic action include energy metabolism, B cells, NK cells and CD4 cells.

show abstract

“…DPP4 is upregulated in liver cirrhosis 18 , 19 , 20 . This is the first demonstration that DPP4 has a pro‐fibrotic role in the liver.…”

Section: Discussionmentioning

confidence: 71%

The pro‐fibrotic role of dipeptidyl peptidase 4 in carbon tetrachloride‐induced experimental liver injury

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Liver sections obtained from mice fed on HFD for 21 days showed by transmission electron microscopy the presence of atypical mitochondria with different volumes (Kahle et al, 2014). Furthermore, NAFLD can lead to mitochondrial dysfunction and apoptosis and fibrosis of hepatocytes (Williams et al, 2015, Garcia-Ruiz & Fernandez-Checa, 2006. These reports are in agreement with our findings on HFD-induced NAFLD in rats that showed degenerated hepatocytes including atypical mitochondria (Fig.…”

Section: Discussionmentioning

confidence: 99%

Differential Therapeutic Effects of Crataegus aronia and Simvastatin on the Hepatocyte Ultrastructure in Hepatic Steatosis

et al. 2017

View full text Add to dashboard Cite

SUMMARY:Complications of fat accumulation in liver, hepatic steatosis such as liver cirrhosis and liver failure are among the common public health problems. We sought to investigate the damage to the hepatocyte ultrastructure induced by high fat diets (HFD) and compared the therapeutic effects at the cellular level of two antioxidant and lipid lowering agents; Crataegus aronia extracts and simvastatin on hepatic steatosis. Rats were either fed with HFD (model group) or low fat diets (LFD) (control group) for 15 weeks before being sacrificed and therapeutic groups started the treatment with these agents after week 11 until the sacrifice day. Harvested liver tissues were examined using transmission electron microscopy (TEM) and liver homogenates were assayed for markers of antioxidative stress that are known to be modulated in liver injury. TEM examinations of the model group showed a profound damage to the hepatocytes compared to the control group as demonstrated by steatosis, damaged mitochondria and vaculated cytoplasm, disrupted rough and smooth endoplasmic reticulum and nuclear membrane, dilated intercellular space between hepatocytes, and alterations in lysosomes. In addition, HFD ameliorated the anti-oxidant glutathione (GSH) and augmented the oxidative stress TBARS biomarkers. Both Crataegus aronia and simvastatin significantly reduced lipids and TBARS, and treated damage to hepatic cells, but hepatocyte structures were differentially responded to these agents. However, only Crataegus aronia induced GSH (p=0.001). We conclude that HFD-induced hepatic steatosis caused a substantial damage to the hepatocyte's ultrastructures, and Crataegus aronia and simvastatin treatments differentially reversed hepatic injuries.

show abstract

“…Rats with DPP4 deficiency have improved bile secretory function in a high fat diet-induced steatosis model[7]. In patients with T2D and/or morbid obesity, circulating DPP4 activity is associated with current apoptosis and liver fibrosis[31]. …”

Section: Discussionmentioning

confidence: 99%

Linagliptin alleviates fatty liver disease in diabetic db/db mice

Мичурина¹,

Ishenko²,

Климонтов³

et al. 2016

WJD

View full text Add to dashboard Cite

AIMTo study the effects of linagliptin on the structural signs of non-alcoholic fatty liver disease (NAFLD) in db/db mice.METHODSMale diabetic db/db mice (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. Intact db/db mice 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.RESULTSIn 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% vs 64.9% ± 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% vs 50.4% ± 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.CONCLUSIONThe DPP4 inhibitor linagliptin alleviates liver steatosis and structural changes in the hepatic microvasculature and lymphatic roots in a model of NAFLD in diabetic db/db mice.

show abstract

Circulating dipeptidyl peptidase‐4 activity correlates with measures of hepatocyte apoptosis and fibrosis in non‐alcoholic fatty liver disease in type 2 diabetes mellitus and obesity: A dual cohort cross‐sectional study

Cited by 49 publications

References 43 publications

The pro‐fibrotic role of dipeptidyl peptidase 4 in carbon tetrachloride‐induced experimental liver injury

The pro‐fibrotic role of dipeptidyl peptidase 4 in carbon tetrachloride‐induced experimental liver injury

Differential Therapeutic Effects of Crataegus aronia and Simvastatin on the Hepatocyte Ultrastructure in Hepatic Steatosis

Linagliptin alleviates fatty liver disease in diabetic db/db mice

Contact Info

Product

Resources

About