Nonalcoholic fatty liver disease (NAFLD) is now the most frequent chronic

Nonalcoholic fatty liver disease (NAFLD) is now the most frequent chronic liver disease in Western Societies affecting one in four adults in the USA and is strongly associated with hepatic insulin resistance a major risk factor in the pathogenesis of type 2 diabetes. for NAFLD-associated hepatic insulin resistance seen in obesity type 2 diabetes and lipodystrophy. INTRODUCTION NAFLD now the most common chronic liver disease in the world with a prevalence of about 20-30% in Western countries is a major risk factor in the development of type 2 diabetes most likely due to its strong association with hepatic insulin resistance (Angulo 2002 Fabbrini et al. 2010 Shulman 2000 In this Perspective we briefly review recent studies in both rodents and humans supporting diacylglycerol-activation of protein kinase Cε (PKCε) as a key pathway responsible for causing NAFLD-associated hepatic insulin resistance. Diacylglycerol-Induced Hepatic Insulin Resistance Mice with targeted BG45 overexpression of lipoprotein lipase (LPL) in the liver develop liver specific steatosis associated with liver specific hepatic insulin resistance demonstrating that hepatic insulin resistance can occur independently of changes in circulating adipocytokines [tumor necrosis factor-α (TNF-α) interleukin-6 (IL-6) resistin adiponectin retinol binding protein-4 (RBP-4) etc.] (Kim et al. 2001 Hepatic steatosis and hepatic insulin resistance can also be induced in mice and rats with three days of high-fat feeding before the development of obesity and raises in circulating adipocytokines (Samuel et al. 2004 With this style of hepatic insulin level of resistance hepatic steatosis was connected with reduced insulin-stimulated insulin receptor substrate-2 (IRS-2) tyrosine phosphorylation from the insulin receptor kinase BG45 resulting in the shortcoming of insulin to activate hepatic glycogen synthesis and suppress hepatic blood sugar production. With this complete case hepatic insulin level of resistance was connected with a rise in hepatic DAG content material. The hyperlink between hepatic DAG build up and hepatic insulin level of resistance could be related to activation of PKCε that was the predominant PKC isoform triggered in liver organ following fat nourishing (Samuel et al. 2004 PKCε can be a member from the PKC family members made up of three different organizations: regular (α βI βII and γ) book (δ ε η and θ) and atypical (ζ and λ) (Newton 2003 PKCε is really a book PKC isoform that includes a very much higher affinity for DAG than the conventional PKC isoforms (Dries et al. 2007 which are activated by calcium binding to the C2 domain which increases the affinity of the C1 domain for DAG subsequently leading to the removal of a pseudosubstrate from the catalytic domain. Phorbol esters have been shown to activate PKCs BG45 and impair activation of the insulin receptor (Pillay et al. 1990 Takayama et al. 1988 DAG has different stereoisomers and it has been previously shown that activation of PKC was mostly due to the sn-1 2 isoform (Rando and Young 1984 The mechanism for lipid-induced insulin resistance is similar to what is observed in skeletal muscle where PKCθ has been shown to be the predominant novel PKC isoform activated during lipid-induced muscle insulin resistance (Griffin et al. 1999 Yu et al. 2002 The molecular mechanisms of DAG activation of PKCε in hepatic insulin resistance are summarized Prkwnk1 in Figure 1. Figure BG45 1 Molecular Mechanism of Diacylglycerol-PKCε Mediated Hepatic Insulin Resistance Further evidence in support of intrahepatic lipid as the mediator of hepatic insulin resistance comes from studies in which high-fat fed rats were treated with low doses of 2 4 (DNP) to promote BG45 mitochondrial energy uncoupling (Samuel et al. 2004 This treatment protected rats from developing hepatic steatosis as well as PKCε activation and hepatic insulin resistance (Samuel et al. 2004 The specific role of PKCε in causing hepatic insulin resistance was directly examined using antisense oligonucleotides (ASO) which act preferentially in the liver and adipose tissue (Crooke 2004 Using a specific PKCε antisense oligonucleotide Samuel lipogenesis leading to an increase in hepatic DAG content. Finally decreased mitochondrial function can also result in the net accumulation of DAGs. Figure 2 Mechanisms of Hepatocellular Diacylglycerol Build up CALORIE CONSUMPTION and Diet Structure The most common trigger for NAFLD in Traditional western Society could be related to energy imbalance where calorie consumption exceeds caloric costs resulting in an.