Table of Contents    
Editorial
 
Relieving hepatic steatosis: Another benefit of dipeptidyl peptidase-4 (DPP4) inhibitors
Zachary Braunstein1, Jixin Zhong2
1Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA.
2Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Article ID: 100036IJHPDZB2015
doi:10.5348/ijhpd-2015-36-ED-11

Address correspondence to:
Jixin Zhong
MD, PhD, Department of Medicine University of Maryland School of Medicine
20 Penn St., S022; Baltimore, MD 21201
USA
Phone: 410-706-3582
Fax: 410-706-3583

Access full text article on other devices

  Access PDF of article on other devices

[HTML Abstract]   [PDF Full Text] [Print This Article]
[Similar article in Pumed] [Similar article in Google Scholar]

How to cite this article
Braunstein Z, Zhong J. Relieving hepatic steatosis: Another benefit of dipeptidyl peptidase-4 (DPP4) inhibitors. Int J Hepatobiliary Pancreat Dis 2015;5:67–69.



Hepatic steatosis is strongly associated with type 2 diabetes (T2DM), both of which are common disorders resulting from obesity [1]. Compared to the general population, there is a higher risk for chronic liver disease and cirrhosis, arising from hepatic steatosis, in diabetic persons [2.3-fold increase of mortality in older onset (diagnosed after age 30) and 4.8-fold increase of mortality in younger onset (diagnosed before age 30)] [2]. Therefore, hepatic steatosis is a key issue in the treatment of T2DM. Furthermore in recent studies, dipeptidyl peptidase-4 (DPP4) inhibition has been suggested to ameliorate hepatic steatosis [3] [4] [5].

Oral delivery of glucose induces a greater insulin response than intravenous delivery, a phenomenon called "incretin effect". This effect is mediated by so called "incretin hormones", including glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), two small peptides produced by enteroendocrine L cells and K cells, respectively [6]. One primary role of incretins is to promote postprandial insulin secretion. They increase insulin biosynthesis through a PDX-1-dependent pathway [7]. These incretins can be rapidly inactivated by DPP4 [8]. DPP4 inhibitors are a novel class of oral anti-diabetic drugs with several available in the market for the treatment of diabetes: sitagliptin (Januvia, marketed by Merck & Co., FDA approved 2006), vildagliptin (Galvus, marketed by Novartis, European Medicines Agency approved 2007), Saxagliptin (Onglyza, marketed by Bristol-Myers Squibb and AstraZeneca, FDA approved 2009), linagliptin (Tradjenta, marketed by Eli Lily Co and Boehringer Ingelheim), and alogliptin (Nesina, marketed by Takeda Pharmaceutical Co., FDA approved 2013).There are also two DPP4 inhibitors that were approved in Japan in 2012: anagliptin (trade name Suiny) and teneligliptin (trade name Tenelia). DPP4 inhibitors have shown mild effect on glycemia lowering, with a 0.4–0.8% lowering of HbA1c [9] [10] [11] However, they are weight neutral, easy to use (oral delivery), and well-tolerated (especially with regards to hypoglycemia) and thus widely utilized in clinic. Both clinical trials and experimental evidence indicate DPP4 inhibitors are safe from a cardiovascular standpoint [12] [13] [14] [15].

In a recent paper published in the June 2015 issue of Diabetes, DPP4 inhibition by MK0626, an analog of des-fluoro-sitagliptin (Merck Research Laboratories, West Point, PA), prevented western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function [3]. We showed that DPP4 inhibition improved liver insulin sensitivity and ameliorated hepatic diacylglycerol accumulation, independent of changes in body weight or adiposity. Triglyceride accumulation in the liver is a major cause of hepatic steatosis and hepatic triglyceride export, via very low density lipoprotein (VLDL), is an important mechanism utilized by the liver to eliminate excessive triglycerides [16]. Western diet resulted in a dramatic reduction in liver triglyceride secretion and MK0626 was shown to partially reverse this effect. VLDL export of triglyceride requires microsomal triglyceride transfer protein (MTTP) and Apolipoprotein B (apoB), both of which increased in MK0626-treated western diet-fed mice. We showed that DPP4 inhibition also reduced hepatic diacylglycerol and triglyceride accumulation by enhancing mitochondrial carbohydrate utilization. Hepatic mitochondrial function was significantly improved in MK0626-treated mice as evidenced by increased pyruvate dehydrogenase (PDH) activity and tricarboxylic acid (TCA) cycle flux. Western diet-induced reduction of sirtuin-1 (Sirt1), an important regulator of mitochondrial function [17], was completely prevented by DPP4 inhibition. Consistent with this, Sirt1-regulated genes (including PGC-1a, CPT-1, TFAM and PPAR-a) increased in MK0626-treated mice. DPP4 inhibition also decreased incomplete palmitate oxidation, a marker of hepatic insulin resistance and mitochondrial dysfunction [18], in western diet-fed mice.

In summary, there are several recent studies suggesting a role of DPP4 inhibitors in improving diabetes-associated fatty liver disease. Both hepatic lipid remodeling and mitochondrial function modulation may perhaps be involved in this process. However, further studies are required to confirm the relieving effect of DPP4 on fatty liver disease. Effect of other DPP4 inhibitors need to be further examined. Although the improving effect of vildagliptin on hepatic steatosis has been observed in a human study with a total of 44 T2DM patients, this effect in humans needs to be confirmed in future studies with a larger sample size.

References
  1. Roden M. Mechanisms of Disease: hepatic steatosis in type 2 diabetes--pathogenesis and clinical relevance. Nat Clin Pract Endocrinol Metab 2006 Jun;2(6):335–48.   [CrossRef]   [Pubmed]    Back to citation no. 1
  2. Moss SE, Klein R, Klein BE. Cause-specific mortality in a population-based study of diabetes. Am J Public Health 1991 Sep;81(9):1158–62.   [CrossRef]   [Pubmed]    Back to citation no. 2
  3. Aroor AR, Habibi J, Ford DA, et al. Dipeptidyl peptidase-4 inhibition ameliorates Western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function. Diabetes 2015 Jun;64(6):1988–2001.   [CrossRef]   [Pubmed]    Back to citation no. 3
  4. Ohyama T, Sato K, Yamazaki Y, et al. MK-0626, a selective DPP-4 inhibitor, attenuates hepatic steatosis in ob/ob mice. World J Gastroenterol 2014 Nov 21;20(43):16227–35.   [CrossRef]   [Pubmed]    Back to citation no. 4
  5. Macauley M, Hollingsworth KG, Smith FE, et al. Effect of vildagliptin on hepatic steatosis. J Clin Endocrinol Metab 2015 Apr;100(4):1578–85.   [CrossRef]   [Pubmed]    Back to citation no. 5
  6. Meier JJ, Gallwitz B, Nauck MA. Glucagon-like peptide 1 and gastric inhibitory polypeptide: potential applications in type 2 diabetes mellitus. BioDrugs 2003;17(2):93–102.   [CrossRef]   [Pubmed]    Back to citation no. 6
  7. Zhong J, Rao X, Rajagopalan S. An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: potential implications in cardiovascular disease. Atherosclerosis 2013 Feb;226(2):305–14.   [CrossRef]   [Pubmed]    Back to citation no. 7
  8. Advani A, Bugyei-Twum A, Connelly KA. Cardiovascular effects of incretins in diabetes. Can J Diabetes 2013 Oct;37(5):309–14.   [CrossRef]   [Pubmed]    Back to citation no. 8
  9. Zhong J, Maiseyeu A, Davis SN, Rajagopalan S. DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition. Circ Res 2015 Apr 10;116(8):1491–504.   [CrossRef]   [Pubmed]    Back to citation no. 9
  10. Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 2012 Mar 12;344:e1369.   [CrossRef]   [Pubmed]    Back to citation no. 10
  11. Park H, Park C, Kim Y, Rascati KL. Efficacy and safety of dipeptidyl peptidase-4 inhibitors in type 2 diabetes: meta-analysis. Ann Pharmacother 2012 Nov;46(11):1453–69.   [CrossRef]   [Pubmed]    Back to citation no. 11
  12. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013 Oct 3;369(14):1317–26.   [CrossRef]   [Pubmed]    Back to citation no. 12
  13. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013 Oct 3;369(14):1327–35.   [CrossRef]   [Pubmed]    Back to citation no. 13
  14. Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev 2014 Dec;35(6):992–1019.   [CrossRef]   [Pubmed]    Back to citation no. 14
  15. Patil HR, Al Badarin FJ, Al Shami HA, et al. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Am J Cardiol 2012 Sep 15;110(6):826–33.   [CrossRef]   [Pubmed]    Back to citation no. 15
  16. Kawano Y, Cohen DE. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol 2013 Apr;48(4):434–41.   [CrossRef]   [Pubmed]    Back to citation no. 16
  17. Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006 Dec 15;127(6):1109–22.   [CrossRef]   [Pubmed]    Back to citation no. 17
  18. Adams SH, Hoppel CL, Lok KH, et al. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J Nutr 2009 Jun;139(6):1073–81.   [CrossRef]   [Pubmed]    Back to citation no. 18

[HTML Abstract]   [PDF Full Text]

Author Contributions:
Zachary Braunstein – Substantial contributions to conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published
Jixin Zhong – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Guarantor of submission
The corresponding author is the guarantor of submission.
Source of support
None
Conflict of interest
Authors declare no conflict of interest.
Copyright
© 2015 Zachary Braunstein et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.