The Role of Hepatic Lipids in Hepatic Insulin Resistance and Type 2 Diabetes

Overview

Journal Nature

Specialty Science

Date 2014 Jun 6

PMID 24899308

Citations 493

Authors

Rachel J Perry

Varman T Samuel

Kitt F Petersen

Gerald I Shulman

Affiliations

Soon will be listed here.

Abstract

Non-alcoholic fatty liver disease and its downstream sequelae, hepatic insulin resistance and type 2 diabetes, are rapidly growing epidemics, which lead to increased morbidity and mortality rates, and soaring health-care costs. Developing interventions requires a comprehensive understanding of the mechanisms by which excess hepatic lipid develops and causes hepatic insulin resistance and type 2 diabetes. Proposed mechanisms implicate various lipid species, inflammatory signalling and other cellular modifications. Studies in mice and humans have elucidated a key role for hepatic diacylglycerol activation of protein kinase Cε in triggering hepatic insulin resistance. Therapeutic approaches based on this mechanism could alleviate the related epidemics of non-alcoholic fatty liver disease and type 2 diabetes.

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References

Benhamed F, Denechaud P, Lemoine M, Robichon C, Moldes M, Bertrand-Michel J . The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. J Clin Invest. 2012; 122(6):2176-94. PMC: 3366390. DOI: 10.1172/JCI41636. View

Weiss E, Galuska D, Khan L, Gillespie C, Serdula M . Weight regain in U.S. adults who experienced substantial weight loss, 1999-2002. Am J Prev Med. 2007; 33(1):34-40. DOI: 10.1016/j.amepre.2007.02.040. View

Xu E, Forest M, Schwab M, Avramoglu R, St-Amand E, Caron A . Hepatocyte-specific Ptpn6 deletion promotes hepatic lipid accretion, but reduces NAFLD in diet-induced obesity: potential role of PPARγ. Hepatology. 2013; 59(5):1803-15. DOI: 10.1002/hep.26957. View

Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G . A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010; 53(2):372-84. DOI: 10.1016/j.jhep.2010.04.008. View

McGuire M, Wing R, Hill J . The prevalence of weight loss maintenance among American adults. Int J Obes Relat Metab Disord. 2000; 23(12):1314-9. DOI: 10.1038/sj.ijo.0801075. View

Zhang C, Chen X, Zhu R, Zhang Y, Yu T, Wang H . Endoplasmic reticulum stress is involved in hepatic SREBP-1c activation and lipid accumulation in fructose-fed mice. Toxicol Lett. 2012; 212(3):229-40. DOI: 10.1016/j.toxlet.2012.06.002. View

Charlton M, Burns J, Pedersen R, Watt K, Heimbach J, Dierkhising R . Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011; 141(4):1249-53. DOI: 10.1053/j.gastro.2011.06.061. View

Kumashiro N, Erion D, Zhang D, Kahn M, Beddow S, Chu X . Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 2011; 108(39):16381-5. PMC: 3182681. DOI: 10.1073/pnas.1113359108. View

Cao H, Maeda K, Gorgun C, Kim H, Park S, Shulman G . Regulation of metabolic responses by adipocyte/macrophage Fatty Acid-binding proteins in leptin-deficient mice. Diabetes. 2006; 55(7):1915-22. DOI: 10.2337/db05-1496. View

10.

Satapati S, Sunny N, Kucejova B, Fu X, He T, Mendez-Lucas A . Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J Lipid Res. 2012; 53(6):1080-92. PMC: 3351815. DOI: 10.1194/jlr.M023382. View

11.

Neschen S, Morino K, Dong J, Wang-Fischer Y, Cline G, Romanelli A . n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator-activated receptor-alpha-dependent manner. Diabetes. 2007; 56(4):1034-41. DOI: 10.2337/db06-1206. View

12.

Pilkis S, El-Maghrabi M, Claus T . Fructose-2,6-bisphosphate in control of hepatic gluconeogenesis. From metabolites to molecular genetics. Diabetes Care. 1990; 13(6):582-99. DOI: 10.2337/diacare.13.6.582. View

13.

Mittendorfer B, Magkos F, Fabbrini E, Mohammed B, Klein S . Relationship between body fat mass and free fatty acid kinetics in men and women. Obesity (Silver Spring). 2009; 17(10):1872-7. PMC: 3319738. DOI: 10.1038/oby.2009.224. View

14.

Hui J, Kench J, Chitturi S, Sud A, Farrell G, Byth K . Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. 2003; 38(2):420-7. DOI: 10.1053/jhep.2003.50320. View

15.

Fabbrini E, Sullivan S, Klein S . Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2009; 51(2):679-89. PMC: 3575093. DOI: 10.1002/hep.23280. View

16.

Roden M, Price T, Perseghin G, Petersen K, Rothman D, Cline G . Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996; 97(12):2859-65. PMC: 507380. DOI: 10.1172/JCI118742. View

17.

Savage D, Murgatroyd P, Chatterjee V, ORahilly S . Energy expenditure and adaptive responses to an acute hypercaloric fat load in humans with lipodystrophy. J Clin Endocrinol Metab. 2004; 90(3):1446-52. DOI: 10.1210/jc.2004-1494. View

18.

Speliotes E, Yerges-Armstrong L, Wu J, Hernaez R, Kim L, Palmer C . Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011; 7(3):e1001324. PMC: 3053321. DOI: 10.1371/journal.pgen.1001324. View

19.

Kleiner D, Brunt E, Van Natta M, Behling C, Contos M, Cummings O . Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005; 41(6):1313-21. DOI: 10.1002/hep.20701. View

20.

Cortes V, Cautivo K, Rong S, Garg A, Horton J, Agarwal A . Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2-/- lipodystrophic mice independent of hepatocyte leptin receptors. J Lipid Res. 2013; 55(2):276-88. PMC: 3886666. DOI: 10.1194/jlr.M045799. View