Apolipoprotein B100 acts as a molecular link between lipid-induced endoplasmic reticulum stress and hepatic insulin resistance #

Abstract

Accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER) results in ER stress and lipid overload-induced ER stress has been implicated in the development of insulin resistance. Here, evidence is provided for a molecular link between hepatic apolipoprotein B100 (apoB100), induction of ER stress, and attenuated insulin signaling. First, in vivo upregulation of hepatic apoB100 by a lipogenic diet was found to be closely associated with ER stress and attenuated insulin signaling in the liver. Direct in vivo overexpression of human apoB100 in a mouse transgenic model further supported the link between excessive apoB100 expression and hepatic ER stress. Human apoB100 transgenic mice exhibited hypertriglyceridemia and hyperglycemia. In vitro, accumulation of cellular apoB100 by free fatty acid ( P erturbations in lipid metabolism and lipid signaling underlie the pathogenesis of a cluster of chronic metabolic diseases, including insulin resistance, type 2 diabetes, fatty liver disease, and atherosclerosis.The atherogenic dyslipidemia commonly associated with insulin-resistant states consists of hypertriglyceridemia, a high level of very low-density lipoprotein (VLDL), a low level of high-density lipoprotein (HDL) cholesterol, 1 and elevated small, low-density lipoprotein (LDL). High dietary fat intake has been shown to induce insulin resistance (IR) and the lipid synthetic rate by way of increased free fatty acid (FFA) flux, as well as assembly and secretion of both VLDL-apolipoprotein B (apoB) and triglyceride (TG) in animal and human models. 2,3 The association of IR and increased VLDL secretion is thought to be derived from increased FFA delivery to the liver resulting from increased lipolysis in adipose tissue, a phenomenon accompanied by increased hepatic lipogenesis, increased hepatic microsomal triglyceride transfer protein (MTP) level and activity, and loss of apoB regulation by insulin.Recent studies implicate hepatic ER stress as a central abnormality linking obesity, hepatic IR, and hepatic steatosis. 4,5 Ozcan et al. 4 have demonstrated that obesityinduced ER stress leads to hepatic IR by activating c-Jun N-terminal kinase (JNK) through inositol-requiring enzyme-1 (IRE-1), with subsequent inhibition of insulin receptor signaling. ER stress has also been linked to increased hepatic lipogenesis. 6,7 However, loss of MTP activity in mouse hepatocytes by either gene disruption or

Different fatty acids inhibit apoB100 secretion by different pathways: unique roles for ER stress, ceramide, and autophagy

“…Su et al proposed that, in hepatocytes, OA induces ER stress by increasing the translocation of newly synthesized apoB into the secretory pathway and, thus, the amount of apoB processed by the ER ( 9 ). On the basis of on our prior studies, we can rule out increases in lipid peroxides and reactive oxygen species as the mechanism for OA-induced ER stress ( 14 ).…”

“…First, ER stress has been shown to stimulate de novo fatty acid synthesis in the liver, adding to the burden of excess fatty acid delivery to the liver (28)(29)(30). Second, ER stress reduces the secretion of apoB100 lipoproteins, interfering with the ability of hepatocytes to export the excess TG that has accumulated ( 6,9 ). TG itself does not appear to be the mediator of fatty acid-induced ER stress in the liver ( 31,32 ) and may instead constitute a neutral form of storage for fatty acids.…”

Ubiquitination regulates the assembly of VLDL in HepG2 cells and is the committing step of the apoB-100 ERAD pathway

“…This suggests that delayed apoB-100 turnover may be the major cause of the ER stress in p97 knockdown cells. Indeed, it was recently proposed that overproduction of the apoB-100 protein may be a "molecular link" between lipidinduced ER stress and hepatic insulin resistance ( 37 ).…”

C/EBP Homologous Protein (CHOP) Contributes to Suppression of Metabolic Genes during Endoplasmic Reticulum Stress in the Liver

“…However, we have previously shown that inhibition of fatty acid oxidation protects the liver from ER stress in vivo (56), suggesting that fatty acid catabolism contributes to ER stress. In addition, because lipogenesis occurs at the ER membrane, it also might compromise ER function and thus be targeted for suppression during UPR activation; at a minimum, triglyceride synthesis and production and secretion by the liver of VLDL lead to ER stress (57). It is conceivable that both anabolic and catabolic lipid fluxes tax the ER and that the UPR is primed to suppress both processes.…”