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

Caviglia, Jorge Matías; Gayet, Constance; Ota, Tsuguhito; Hernandez‐Ono, Antonio; Conlon, Donna; Jiang, Hongfeng; Fisher, Edward A.; Ginsberg, Henry N.

doi:10.1194/jlr.m016931

Cited by 79 publications

(63 citation statements)

References 56 publications

(82 reference statements)

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“…In contrast, docosahexaenoic acid inhibits B100 without induction of ER stress and targets B100 for autophagic degradation. 46 Severely dysfunctional hepatocytes, as occurs with streptozotocin-induced diabetes mellitus 47 or with endstage diabetes mellitus in aged Zucker diabetic fatty rats, 48 have reduced apoB output likely because of the inability to synthesize and properly fold apoB into a form that can accept lipids.…”

Section: Insulin Modulation Of Hepatic Vldl Via Induction Of Apob Degmentioning

confidence: 99%

“…44 Various FA have differing effects in McArdle RH-7777 cells on apoB secretion with different time courses, 45,46 concentration dependence, and mechanisms. 46 Palmitate and oleate decrease B100 secretion through induction of ER stress through a protein kinase Rlike ER kinase pathway, which is unrelated to induction of autophagy. In contrast, docosahexaenoic acid inhibits B100 without induction of ER stress and targets B100 for autophagic degradation.…”

Section: Insulin Modulation Of Hepatic Vldl Via Induction Of Apob Degmentioning

confidence: 99%

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Selective Hepatic Insulin Resistance, VLDL Overproduction, and Hypertriglyceridemia

Sparks

Adeli

2012

ATVB

187

125

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A central feature of metabolic syndrome is hepatic hypersecretion of very low-density lipoprotein (VLDL), which results in hypertriglyceridemia (HTG), a consistent finding associated with obesity and type 2 diabetes mellitus. Under physiological conditions, insulin signaling regulates VLDL production by targeting apolipoprotein (apo) B for degradation and limiting apoB synthesis.1 Pancreatic release of insulin into the portal vein after eating reduces VLDL output during the postprandial period allowing for transient triglyceride (TG) storage for future secretion. This is consistent with insulin acting as an anabolic hormone stimulating energy storage in both liver and fat. Because of reduced hepatic secretion of VLDL, there is less competition for lipolysis with intestinal lipoproteins resulting in their preferential clearance. Loss of this acute pathway may be the earliest consequence of overnutrition and with it is the loss of the cyclical nature of VLDL production during the postprandial transition. There is then continuous secretion of VLDL and packaging of excess TG into larger sized (VLDL1) and more numerous VLDL particles, inducing HTG. Insulin induction of de novo lipogenesis (DNL) favors TG synthesis and occurs independent of effects on apoB. With insulin resistance, more apoB is available and along with stimulation of DNL, there is hypersecretion of VLDL1. In classical forms of insulin resistance, transcriptional effects increase VLDL production and occur with enhanced gluconeogenesis and forkhead box O1 (FoxO1) activity.2-4 Sustained nuclear localization of FoxO1 increases expression of microsomal triglyceride transfer protein (MTP) 4 and apolipoprotein C-III (apoC-III) 5 resulting in substantial increases in VLDL production above and beyond loss of acute VLDL regulation.2 This review summarizes current understanding of insulin action and insulin resistance related to the complex relationships of apoB and TG in formation of VLDL. This article accompanies the ATVB in Focus: New Developments in Hepatic LipoproteinProduction and Clinical Relevance series that was published in the May 2012 issue. VLDL Assembly and Hepatic VLDL OverproductionVLDL assembly is initiated by the synthesis of B100 (Figure 1), a 550 kDa protein or its shorter form, B48, the protein product of edited apoB mRNA. Editing is a process that introduces a stop codon in the apoB transcript, and in humans this occurs in the intestine. In other species, including mouse and rat, liver makes Abstract-Insulin plays a central role in regulating energy metabolism, including hepatic transport of very low-density lipoprotein (VLDL)-associated triglyceride. Hepatic hypersecretion of VLDL and consequent hypertriglyceridemia leads to lower circulating high-density lipoprotein levels and generation of small dense low-density lipoproteins characteristic of the dyslipidemia commonly observed in metabolic syndrome and type 2 diabetes mellitus. Physiological fluctuations of insulin modulate VLDL secretion, and insulin inhibition of VLDL secretion upon...

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Section: Insulin Modulation Of Hepatic Vldl Via Induction Of Apob Degmentioning

confidence: 99%

Section: Insulin Modulation Of Hepatic Vldl Via Induction Of Apob Degmentioning

confidence: 99%

Selective Hepatic Insulin Resistance, VLDL Overproduction, and Hypertriglyceridemia

Sparks

Adeli

2012

ATVB

187

125

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“…lipid synthesis (during cotranslational translocation across the ER) prevents Apo B membrane from slowing or immobilizing, which favors its elongation . Of particular interest, a high physiologic concentration of lipids, provided over longer periods, induces ER stress that decreases the secretion of Apo B-100 ( 144,145 ). It is recognized that the assembly of TG-rich lipoprotein occurs in two steps, one cotranslational (the fi rst step) and another posttranslational (the second step) where the larger amount of TG is added, likely via fusion of a primordial Apo B lipoprotein particle with an Apo B-free TG droplet in the secretory pathway ( 146 ) ( Fig.…”

Section: Apo B Expression In Different Tissues and During Human Develmentioning

confidence: 99%

Insights from human congenital disorders of intestinal lipid metabolism

Lévy

2015

Journal of Lipid Research

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“…The effect of autophagy on various biological effects to the liver [18][19][20][21] has been recently studied. Alcohol treatment to CYP2E1 expressing HepG2 cells decreased autophagy while inducing steatosis [5].…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P4502E1, Oxidative Stress, JNK, and Autophagy in Acute Alcohol-Induced Fatty Liver

Cederbaum¹

2014

Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging

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Binge alcohol drinking induces hepatic steatosis. Recent studies showed that chronic ethanolinduced fatty liver was, at least in part, CYP2E1 dependent. The mechanism of acute alcohol induced steatosis and whether CYP2E1 plays any role is still unclear. Increasing oxidative stress by alcohol can activate the JNK MAP kinase signaling pathway, suggesting that JNK might be a target for prevention of alcohol induced steatosis. We used CYP2E1 knockout (KO) mice, a JNK inhibitor, and JNK1 or JNK2 knockout mice to test the role of CYP2E1, JNK, and the individual role of JNK1 and JNK2 in acute alcohol-induced steatosis. In wild type (WT) mice, acute alcohol activates CYP2E1 and increases oxidative stress, which reciprocally increases activation of the JNK signaling pathway. Acute alcohol-induced fatty liver and oxidative stress was blunted in CYP2E1 KO mice and by the JNK inhibitor in WT mice. The antioxidant N-acetylcysteine decreased the acute alcohol induced oxidative stress, activation of JNK and the steatosis but not the activation of CYP2E1. Acute alcohol decreased autophagy and increased expression of SREBP, effects blocked by the JNK inhibitor. Acute alcohol-induced fatty liver was the same in either JNK1 or JNK2 KO mice as WT mice, thus either JNK1 or JNK2 per se is sufficient in induction of steatosis by acute alcohol.Conclusion-acute alcohol elevation of CYP2E1, oxidative stress and activation of JNK interact to lower autophagy and increase lipogenic SREBP resulting in fatty liver.

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

Cited by 79 publications

References 56 publications

Selective Hepatic Insulin Resistance, VLDL Overproduction, and Hypertriglyceridemia

Selective Hepatic Insulin Resistance, VLDL Overproduction, and Hypertriglyceridemia

Insights from human congenital disorders of intestinal lipid metabolism

Cytochrome P4502E1, Oxidative Stress, JNK, and Autophagy in Acute Alcohol-Induced Fatty Liver

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