Infusion of Glucose and Lipids at Physiological Rates Causes Acute Endoplasmic Reticulum Stress in Rat Liver

Abstract

Endoplasmic reticulum (ER) stress has recently been implicated as a cause for obesity‐related insulin resistance; however, what causes ER stress in obesity has remained uncertain. Here, we have tested the hypothesis that macronutrients can cause acute (ER) stress in rat liver. Examined were the effects of intravenously infused glucose and/or lipids on proximal ER stress sensor activation (PERK, eIF2‐α, ATF4, Xbox protein 1 (XBP1s)), unfolded protein response (UPR) proteins (GRP78, calnexin, calreticulin, protein disulphide isomerase (PDI), stress kinases (JNK, p38 MAPK) and insulin signaling (insulin/receptor substrate (IRS) 1/2 associated phosphoinositol‐3‐kinase (PI3K)) in rat liver. Glucose and/or lipid infusions, ranging from 23.8 to 69.5 kJ/4 h (equivalent to between ∼17% and ∼50% of normal daily energy intake), activated the proximal ER stress sensor PERK and ATF6 increased the protein abundance of calnexin, calreticulin and PDI and increased two GRP78 isoforms. Glucose and glucose plus lipid infusions induced comparable degrees of ER stress, but only infusions containing lipid activated stress kinases (JNK and p38 MAPK) and inhibited insulin signaling (PI3K). In summary, physiologic amounts of both glucose and lipids acutely increased ER stress in livers 12‐h fasted rats and dependent on the presence of fat, caused insulin resistance. We conclude that this type of acute ER stress is likely to occur during normal daily nutrient intake.

Endoplasmic Reticulum Stress in Nonalcoholic Fatty Liver Disease

“…Activation of the UPR has been observed in liver and/or adipose tissue of dietary and genetic animal models of obesity, many of which include features of NAFLD (5,86,130). Currently only one study has compared markers of UPR activation in humans with or without NAFLD (96).…”

“…Elevated circulating free fatty acids are a characteristic feature of NAFLD and are positively correlated with liver disease severity (77). A growing body of evidence has demonstrated that elevated free fatty acids-in particular, long-chain saturated fatty acids-induce ER stress and activation of the UPR in liver cells (5,82,134). Glycosylation is an essential ER luminal modification for proper stability, folding, translocation, and function of many proteins (50).…”

Cell Death and Survival Through the Endoplasmic Reticulum- Mitochondrial Axis

“…In the presence of high cellular sterol concentrations SCAP retains SREBP at the ER membrane. When sterol concentrations are low, SCAP escorts SREBP to the Golgi for proteolytic activation of SREBP as a transcription factor that promotes expression of genes involved in the cholesterol synthesis, thus restoring homeostasis [13,14].…”

“…In the presence of high cellular sterol concentrations SCAP retains SREBP at the ER membrane. When sterol concentrations are low, SCAP escorts SREBP to the Golgi for proteolytic activation of SREBP as a transcription factor that promotes expression of genes involved in the cholesterol synthesis, thus restoring homeostasis [13,14].The ability of the ER to sense cellular stress facilitates cellular adaptation to a changing environment. In the early phase, the UPR is triggered as a compensatory mechanism to reestablish ER homeostasis and avoid cellular damage.…”

“…In addition to intraorganellar signals, numerous factors external to the ER can induce UPR. For instance, physiological levels of post-prandial lipid and glucose concentrations have been shown to induce acute ER stress, highlighting the metabolic and physiological importance of this pathway [14].Three major signaling pathways mediate the UPR. The upstream sensors are inositolrequiring protein 1 alpha (IRE1α), eukaryotic translation initiation factor 2-alpha kinase (PERK) and activating transcription factor 6 (ATF6).…”