Expression and Significance of Lipin1 and AMPKα in Hepatic Insulin Resistance in Diet-Induced Insulin Resistance Rats

Abstract

Background:

Lipin1, a lately indentified adipokine, may link obesity with insulin resistance and diabetes. The present study aimed to investigate the changes and significance of lipin1 expression and lipin1-AMPK signaling in diet-induced hepatic insulin resistance.

Methods:

24 4-week-old Male Wistar rats were randomly divided into 2 groups: (1) control group (CO), (2) high-fat diet group (HF). Insulin sensitivity was evaluated by hyperinsulinemic-euglycemic clamp technique. The mRNA levels of α1 and α2 subunit of AMPKα as well as Lipin1 were measured using Real-time RT-PCR. The activities of AMPKα and Akt were evaluated by detection of p-AMPKα (Thr-172) and p-Akt (ser473) by Western blot.

Results:

After treatment of 4 months, HF group showed significantly increased levels of body weight, fasting plasma glucose and insulin levels; Plasma and liver total cholesterol (TC), triglycerides (TG) levels were also markedly elevated; Lipin1 expression at both mRNA and protein levels were significantly deceased. Compared with CO group, the mRNA and protein levels of AMPKα1 and AMPKα2 were not changed, whereas the p-AMPK (Thr-172) and p-AKT (ser473) levels in liver were significantly decreased in HF group.

Conclusions:

These findings indicated that the decrease in lipin1 expression and AMPKα activation may contribute to hepatic insulin resistance in diet-induced obese rats.

Key words

hepatic Insulin resistance - AMP-activated protein kinase - lipin1 - Lpin1

*

^*  These authors contribute equally to this work.

• References

• 1 Carling D, Sanders MJ, Woods A. The regulation of AMP-activated protein kinase by upstream kinases. Int J Obes (Lond) 2008; 32 (Suppl. 04) S55-S59 [PubMed:18719600]
• 2 Chen Z, Gropler MC, Norris J et al. Alterations in hepatic metabolism in fld mice reveal a role for lipin1 in regulating VLDL-triacylglyceride secretion. Arterioscler Thromb Vasc Biol 2008; 28 (10) 1738-1744 [PubMed:18669885]
• 3 Donkor J, Sariahmetoglu M, Dewald J et al. Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns. J BiolChem 2007; 282: 3450-3457 [PubMed:17158099]
• 4 Donkor J, Sparks LM, Xie H et al. Adipose tissue lipin-1 expression is correlated with peroxisome proliferator-activated receptor alpha gene expression and insulin sensitivity in healthy young men. J Clin Endocrinol Metab Jan 2008; 93 (01) 233-239 [PubMed:17925338]
• 5 Gonzalez E, McGraw TE. Insulin signaling diverges into Akt-dependent and -independent signals to regulate the recruitment/docking and the fusion of GLUT4 vesicles to the plasma membrane. Mol Biol Cell Oct 2006; 17 (10) 4484-4493 [PubMed: 16914513]
• 6 Finck BN, Gropler MC, Chen Z et al. Lipin1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab 2006; 4: 199 -210 [PubMed:16950137]
• 7 Fryer LG, Carling D. AMP-activated protein kinase and the metabolic syndrome. Biochem Soc Trans Apr 2005; 33 (02) 362-366 [PubMed: 15787607]
• 8 Han GS, Wu WI, Carman GM. The Saccharomyces cerevisiae lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme. J Biol Chem 2006; 281: 9210-9218 [PubMed:16467296]
• 9 Higashida K, Higuchi M, Terada S. Potential role of lipin-1 in exercise-induced mitochondrial biogenesis. Biochem Biophys Res Commun 2008; 26; 374 (03) 587-591 [PubMed:18656451]
• 10 Huffman TA, Mothe-Satney I, Lawrence Jr JC. Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin. Proc Natl Acad Sci USA 2002; 22:99 (02) 1047-1052 [PubMed:11792863]
• 11 Lele RD. Pro-insulin, C peptide, glucagon, adiponectin, TNF alpha, AMPK: neglected players in type 2 diabetes mellitus. J Assoc Physicians India 2010; 58 (30) 35-40 [PubMed:20649096]
• 12 Machado RM, Stefano JT, Oliveira CP et al. Intake of trans fatty acids causes nonalcoholic steatohepatitis and reduces adipose tissue fat content. J Nutr 2010; 140 (06) 1127-1132 [PubMed:20357081]
• 13 Morris DL, Rui L. Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab 2009; 297 (06) E1247-1259 [PubMed:19724019]
• 14 Muniyappa R, Lee S, Chen H et al. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab Jan 2008; 294 (01) E15-26 [PubMed:17957034]
• 15 Muse ED, Obici S, Bhanot S et al. Role of resistin in diet-induced hepatic insulin resistance. J Clin Invest 2004; 114 (02) 232-239 [PubMed:15254590]
• 16 Péterfy M, Harris TE, Fujita N et al. Insulin-stimulated interaction with 14-3-3 promotes cytoplasmic localization of lipin-1 in adipocytes. J Biol Chem 2010; 285 (06) 3857-3864 [PubMed: 19955570]
• 17 Peterfy M, Phan J, Reue K. Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis. J Biol Chem 2005; 280 (38) 32883-32889 [PubMed:16049017]
• 18 Phan J, Reue K. Lipin, a lipodystrophy and obesity gene. Cell Metab 2005; 1 (01) 73-83 [PubMed:16054046]
• 19 Reue K, Dwyer JR. Lipin proteins and metabolic homeostasis. J Lipid Res 2009; 50 (Suppl) S109-S114 [PubMed: 18941140]
• 20 Suviolahti E, Reue K, Cantor RM et al. Cross-species analyses implicate lipin1 involvement in human glucose metabolism. Hum Mol Genet 2006; 15: 377-386 [PubMed:16357106]
• 21 Van Harmelen V, Ryden M, Sjolin E et al. A role of lipin in humanobesity and insulin resistance: relation to adipocyte glucose transport and GLUT4 expression. J Lipid Res 2007; 48: 201-206 [PubMed:17035674]
• 22 Waki H, Park KW, Mitro N et al. The small molecule harmine is an anti-diabetic cell-type specific regulator of PPARgamma expression. Cell Metab 2007; 5 (05) 357-370 [PubMed:17488638]
• 23 Yao-Borengasser A, Rasouli N, Varma V et al. Lipin expression is attenuated in adipose tissue of insulin-resistant human subjects and increases with peroxisome proliferator–activated receptor gamma activation. Diabetes 2006; 55: 2811-2818 [PubMed:17003347]
• 24 Zdychová J, Komers R. Emerging role of Akt kinase/protein kinase B signaling in pathophysiology of diabetes and its complications. Physiol Res 2005; 54 (01) 1-16 [PubMed: 15717836]
• 25 Zhang BB, Zhou G, Li C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab 2009; 9 (05) 407-416 [PubMed: 19416711]
• 26 Zhang M, Lv XY, Li J et al. The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Exp Diabetes Res 2008; 2008: 704045-704054 [PubMed:19132099]