Sitagliptin attenuates methionine/choline-deficient diet-induced steatohepatitis.
OBJECTIVE
Accumulating evidence suggests that inhibitors of dipeptidyl peptidase-4 (DPP-4), such as sitagliptin, may play an important role in the prevention of non-alcoholic steatohepatitis (NASH). This study was conducted to elucidate whether sitagliptin could prevent steatohepatitis by inhibiting pathways involved in hepatic steatosis, inflammation, and fibrosis.


METHODS
C57BL/6 mice were fed a methionine/choline-deficient (MCD) diet with or without supplement with sitagliptin for 5 weeks. Liver and adipose tissue from mice were examined histologically and immunohistochemically to estimate the effect of sitagliptin on the development of NASH.


RESULTS
Supplementation with sitagliptin resulted in significant improvement of MCD diet-induced fat accumulation in the liver. In addition, sitagliptin treatment lowered fatty acid uptake, expression of VLDL receptor and hepatic triglyceride content. Sitagliptin also effectively attenuated MCD diet-induced hepatic inflammation, endoplasmic reticulum (ER) stress, and liver injury, as evidenced by reduced proinflammatory cytokine levels, ER stress markers, and TUNEL staining. Expression of CYP2E1 and 4NHE were strongly increased by the MCD diet, but this effect was successfully prevented by sitagliptin treatment. Furthermore, sitagliptin significantly decreased levels of MCD diet-induced fibrosis-associated proteins such as fibronectin and α-SMA in the liver. Inflammatory and atrophic changes of adipose tissue by MCD diet were restored by sitagliptin treatment.


CONCLUSIONS
Sitagliptin attenuated MCD diet-induced hepatic steatosis, inflammation, and fibrosis in mice through amelioration of mechanisms responsible for the development of NASH, including CD36 expression, NF-κB activation, ER stress, CYP2E1 expression, and lipid peroxidation. Treatment with sitagliptin may represent an effective approach for the prevention and treatment of NASH.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
Yun-A
YA
Jung
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Yeon-Kyung
YK
Choi
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Gwon-Soo
GS
Jung
Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
Hye-Young
HY
Seo
Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
Hye-Soon
HS
Kim
Division of Gastroenterology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
Byoung Kuk
BK
Jang
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Jung-Guk
JG
Kim
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
In-Kyu
IK
Lee
Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea. Electronic address: mdkmk@dsmc.or.kr.
Mi-Kyung
MK
Kim
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea. Electronic address: kpark@knu.ac.kr.
Keun-Gyu
KG
Park
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002796:Choline Deficiency / Q000150:complications*; D004032:Diet / Q000009:adverse effects*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D059865:Endoplasmic Reticulum Stress; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D015227:Lipid Peroxidation / Q000502:physiology; D008103:Liver Cirrhosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000627:therapeutic use*; D014280:Triglycerides / Q000378:metabolism
D015415:Biomarkers; D054873:Dipeptidyl-Peptidase IV Inhibitors; D016328:NF-kappa B; D011719:Pyrazines; D012333:RNA, Messenger; D014230:Triazoles; D014280:Triglycerides; D008715:Methionine; D000068900:Sitagliptin Phosphate
DPP-4 inhibitor; GLP-1; MCD diet; Non-alcoholic steatohepatitis (NASH); Sitagliptin