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JSM Gastroenterology and Hepatology

Understanding the Pathogenesis of Insulin Resistance in Non-Alcoholic and Alcoholic Liver Diseases

Editorial | Open Access | Volume 1 | Issue 1

Corresponding Authors
CITATION

Carr RM (2013) Understanding the Pathogenesis of Insulin Resistance in Non-Alcoholic and Alcoholic Liver Diseases. JSM Gastroenterol Hepatol 1(1): 1002.

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) cause significant morbidity and mortality in affected patients and are common causes of liver failure worldwide [1]. NAFLD and ALD are histologically indistinguishable by conventional methods but their disease courses are quite divergent. In particular, ALD patients with steatohepatitis have a more rapid progression to advanced liver disease than NAFLD patients with steatohepatitis [2].

Our research program is focused on understanding both the similarities and differences between the biology of NAFLD and ALD using experimental models. Specifically, we employ both genetic mouse models and cellular models to investigate how lipids and their associated proteins cause insulin resistance, a known predictor of disease progression in both NAFLD and ALD.

We have thus far demonstrated a key role of lipid droplet proteins in the pathogenesis of insulin resistance in both NAFLD and ALD experimental models. Lipid droplet proteins are proteins associated with the phospholipid monolayer of lipid droplets [3]. In the liver, the Perilipin family of lipid droplet proteins predominates [4]. We have demonstrated that these lipid droplet proteins have important functions in energy homeostasis including in reducing glucose and insulin sensitivity [5,6]. Perilipin 2 (Plin2) is the predominant hepatic Perilipin protein, and Perilipin 1 (Plin1) is de novo expressed in human NAFLD [4]. In a small pilot study examining liver sections from adults and children with hepatic steatosis, we observed an increase in Plin1 and Plin2 immunostaining in patients with nonalcoholic steatohepatitis (NASH) compared with NAFLD simple steatosis and non-steatotic control sections. Moreover, Plin1 expression correlated with NASH but not Hepatitis C, a common steatohepatitic disease [7]. In our experimental ALD model, we observed an upregulation of Plin2 in whole liver lysates of ethanol-fed mice. Upregulation of Plin2 coincides with the onset of hepatic steatosis, glucose intolerance and insulin resistance [8]. Plin2 is also a reliable lipid droplet marker in alcohol fed rats [9], in mice fed a high fat, ethanol diet [10], and in WIF-B cells treated with oleate and ethanol [11]. Our ongoing research aims to understand the mechanisms by which lipids and lipid droplet proteins promote insulin resistance in NAFLD and ALD.

One mechanism by which lipids may promote insulin resistance in NAFLD and ALD is through the action of so-called “toxic” lipid metabolites. In NAFLD, the lipid metabolites diacylglycerol, ceramides, lysophosphatidic acid and fatty acyl CoA have been associated with impaired insulin signaling independent of triglyceride accumulation [12-17]; while in ALD, ceramides are suspected [18,19]. Indeed, our research shows an increase in diacylglycerol and ceramides in experimental NAFLD and ALD, respectively [5,8]. Diacylglycerol impairs insulin signaling through activation of PKC-ε activation and reduced IRS2 tyrosine phosphorylation [20]; while ceramides, through their activation of protein phosphatase 2A, inhibit the phosphorylation of Akt, a key downstream event in insulin signaling [21,22]. Our research program will further investigate the specific role of these lipid species in the pathogenesis of NAFLD and ALD.

Success of our research program will be measured by the identification of key mediators of insulin resistance in NAFLD and ALD which can ultimately be used as both diagnostic tools for the pathologic distinction of NAFLD and ALD and as therapeutic targets for the amelioration of disease in NAFLD and ALD patients.

REFERENCES

1. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011; 141: 1249-53.

2. Dam-Larsen S, Becker U, Franzmann MB, Larsen K, Christoffersen P, et al. Final results of a long-term, clinical follow-up in fatty liver patients. Scand J Gastroenterol. 2009; 44: 1236-43.

3. Bickel PE, Tansey JT, Welte MA. PAT proteins, an ancient family of lipid droplet proteins that regulate cellular lipid stores. Biochim Biophys Acta. 2009; 1791: 419-40.

4. Straub BK, Stoeffel P, Heid H, Zimbelmann R, Schirmacher P. Differential pattern of lipid droplet-associated proteins and de novo perilipin expression in hepatocyte steatogenesis. Hepatology. 2008; 47: 1936-46.

5. Carr RM, Patel RT, Rao V, Dhir R, Graham MJ, Reduction of TIP47 improves hepatic steatosis and glucose homeostasis in mice. Am J Physiol Regul Integr Comp Physiol. 2012; 302: 996-1003.

6. Varela GM, Antwi DA, Dhir R, Yin X, Singhal NS, et al. Inhibition of ADRP  prevents diet-induced insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2008; 295: 621-8.

7. Dhir R KM, Carr RM, Comerford M, Chalasani NP, Ahima RS. Differential expression of Plin1 and Plin2 in fatty liver disease in adults and children. AASLD. 2012.

8. Carr RM, Dhir R, Yin X, Agarwal B, Ahima RS. Temporal effects of ethanol consumption on energy homeostasis, hepatic steatosis, and insulin sensitivity in mice. Alcohol Clin Exp Res. 2013; 37: 1091-9.

9. Mak KM, Ren C, Ponomarenko A, Cao Q, Lieber CS. Adipose differentiation-related protein is a reliable lipid droplet marker in alcoholic fatty liver of rats. Alcohol Clin Exp Res. 2008; 32: 683-9.

10. Orlicky DJ, Roede JR, Bales E, Greenwood C, Greenberg A, Chronic ethanol consumption in mice alters hepatocyte lipid droplet properties. Alcohol Clin Exp Res. 2011; 35: 1020-33.

11. McVicker BL, Rasineni K, Tuma DJ, McNiven MA, Casey CA. Lipid droplet accumulation and impaired fat efflux in polarized hepatic cells: consequences of ethanol metabolism. Int J Hepatol. 2012; 2012: 978136.

12. Erion DM, Shulman GI. Diacylglycerol-mediated insulin resistance. Nat Med. 2010; 16: 400-2.

13. Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 2007; 167-79.

14. Kotronen A, Seppänen-Laakso T, Westerbacka J, Kiviluoto T, Arola J, et al. Hepatic stearoyl-CoA desaturase (SCD)-1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver. Diabetes. 2009; 58: 203-8.

15. Li LO, Klett EL, Coleman RA. Acyl-CoA synthesis, lipid metabolism and lipotoxicity. Biochim Biophys Acta. 2010; 1810: 246-51.

16. Nagle CA, Klett EL, Coleman RA. Hepatic triacylglycerol accumulation and insulin resistance. J Lipid Res. 2009; 50: 74-9.

17. Samuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, et al. Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Invest. 2007; 117: 739-45.

18. Zhao Z, Yu M, Crabb D, Xu Y, Liangpunsakul S. Ethanol-induced alterations in fatty acid-related lipids in serum and tissues in mice. Alcohol Clin Exp Res. 2011; 35: 229-34.

19. Liangpunsakul S, Rahmini Y, Ross RA, Zhao Z, Xu Y, et al. Imipramine blocks ethanol-induced ASMase activation, ceramide generation, and PP2A activation, and ameliorates hepatic steatosis in ethanol-fed mice. Am J Physiol Gastrointest Liver Physiol. 2012; 302: 515-23.

20. Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004; 279: 32345-53.

21. Dobrowsky RT, Kamibayashi C, Mumby MC, Hannun YA. Ceramide activates heterotrimeric protein phosphatase 2A. J Biol Chem. 1993; 268: 15523-30.

22. Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008; 9: 139-50.

Carr RM (2013) Understanding the Pathogenesis of Insulin Resistance in Non-Alcoholic and Alcoholic Liver Diseases. JSM Gastroenterol Hepatol 1(1): 1002.

Received : 07 Nov 2013
Accepted : 08 Nov 2013
Published : 11 Nov 2013
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