Regulation of Hepatic Apolipoprotein B-lipoprotein Assembly and Secretion by the Availability of Fatty Acids

Zhang, Yuanli; Hernandez‐Ono, Antonio; Ko, Carol; Yasunaga, Koichi; Huang, Li‐Shin; Ginsberg, Henry N.

doi:10.1074/jbc.m400220200

Cited by 87 publications

(21 citation statements)

References 71 publications

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“…It is not surprising, therefore, that although the regulation of the assembly of VLDL is complex 3, 26, 28, 29 , the availability of hepatic TG is a potent factor regulating TG secretion. Increased delivery of either albumin-bound FA or TGFA-enriched remnant lipoproteins to cultured hepatocytes 29, 38-40 , perfused livers 41, 42 , or livers in vivo 43 can increase the secretion of both TG and apoB. Increased numbers of VLDL particles that are either the same size or larger are secreted.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein B Secretion Is Regulated by Hepatic Triglyceride, and Not Insulin, in a Model of Increased Hepatic Insulin Signaling

Moon

Hernandez‐Ono

Stiles

et al. 2012

ATVB

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Objective States of insulin resistance, hyperinsulinemia, and hepatic steatosis are associated with increased secretion of triglycerides (TG) and apolipoprotein B (apoB), even though insulin targets apoB for degradation. We used hepatic-specific (h) Pten knockout (ko) mice, with increased hepatic insulin signaling, to determine the relative roles of insulin signaling and hepatic TG in regulating apoB secretion. Results/Methods TG and apoB secretion were elevated in hPten-ko mice. When hepatic TG was reduced by inhibition of DGAT1/DGAT2 or SREBP-1c, both TG and apoB secretion fell without changes in hepatic insulin signaling. Acute reconstitution of hPten reduced hepatic TG content and both TG and apoB secretion fell within 4 days despite decreased hepatic insulin signaling. Acute depletion of hepatic Pten by adenoviral introduction of Cre into Pten Floxed mice caused steatosis within 4 days, and secretion of TG and apoB both increased despite increased hepatic insulin signaling. Even when steatosis after acute Pten depletion was prevented by pre-treatment with SREBP-1c ASO, apoB secretion was not reduced after 4 days. Ex vivo results were in primary hepatocytes were similar. Conclusion Either hepatic TG is the dominant regulator of apoB secretion or any inhibitory effects of hepatic insulin signaling on apoB secretion is very short-lived.

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein B Secretion Is Regulated by Hepatic Triglyceride, and Not Insulin, in a Model of Increased Hepatic Insulin Signaling

Moon

Hernandez‐Ono

Stiles

et al. 2012

ATVB

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“…Intravenous infusions of oleic acid (OA) bound to albumin stimulate apoB secretion in mice without stimulating TG secretion, whereas delivery of a similar absolute amount of OA derived from endocytosis of remnant-like particles during infusion of Intralipid (an emulsion of TG and phospholipids [PL]) did not affect apoB secretion (20). Several fold more OA had to be delivered via Intralipid to stimulate apoB secretion, and at those levels of OA, TG secretion was also increased (20).…”

Section: Sources Of Hepatic Tg In Normal and Ir Statesmentioning

confidence: 99%

Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance

Choi

Ginsberg

2011

Trends in Endocrinology & Metabolism

317

251

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Insulin resistance (IR) not only affects regulation of carbohydrate metabolism, but all aspects of lipid and lipoprotein metabolism. IR is associated with increased secretion of very low density lipoproteins (VLDL) and increased plasma triglycerides, as well as hepatic steatosis, despite the increased VLDL secretion. Here, we link IR with increased VLDL secretion and hepatic steatosis at both the physiologic and molecular levels. Increased VLDL secretion, together with the downstream effects on high density lipoprotein cholesterol and low density lipoprotein size is pro-atherogenic. Hepatic steatosis is a risk for steatohepatitis and cirrhosis. Understanding the complex inter-relationship between IR and these abnormalities of liver lipid homeostasis may provide insights relevant to new therapies for these increasing clinical problems.

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“…ApoB is unique in its ability to associate with neutral lipids from cellular stores, and high levels of fatty acid substrates for TG biosynthesis can increase hepatic very low density lipoprotein (VLDL) assembly[18]-[23]. Mutations in the amino terminus of apoB that prevent the initiation of assembly also reduce hepatic VLDL secretion[24],[25].…”

Section: Apolipoprotein B and The Assembly Of Very Low Density Lipoprmentioning

confidence: 99%

Apolipoprotein B100 quality control and the regulation of hepatic very low density lipoprotein secretion

Fisher¹,

Lake²,

McLeod³

2014

J Biomed Res

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Apolipoprotein B (apoB) is the main protein component of very low density lipoprotein (VLDL) and is necessary for the assembly and secretion of these triglyceride (TG)-rich particles. Following release from the liver, VLDL is converted to low density lipoprotein (LDL) in the plasma and increased production of VLDL can therefore play a detrimental role in cardiovascular disease. Increasing evidence has helped to establish VLDL assembly as a target for the treatment of dyslipidemias. Multiple factors are involved in the folding of the apoB protein and the formation of a secretion-competent VLDL particle. Failed VLDL assembly can initiate quality control mechanisms in the hepatocyte that target apoB for degradation. ApoB is a substrate for endoplasmic reticulum associated degradation (ERAD) by the ubiquitin proteasome system and for autophagy. Efficient targeting and disposal of apoB is a regulated process that modulates VLDL secretion and partitioning of TG. Emerging evidence suggests that significant overlap exists between these degradative pathways. For example, the insulin-mediated targeting of apoB to autophagy and postprandial activation of the unfolded protein response (UPR) may employ the same cellular machinery and regulatory cues. Changes in the quality control mechanisms for apoB impact hepatic physiology and pathology states, including insulin resistance and fatty liver. Insulin signaling, lipid metabolism and the hepatic UPR may impact VLDL production, particularly during the postprandial state. In this review we summarize our current understanding of VLDL assembly, apoB degradation, quality control mechanisms and the role of these processes in liver physiology and in pathologic states.

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Regulation of Hepatic Apolipoprotein B-lipoprotein Assembly and Secretion by the Availability of Fatty Acids

Cited by 87 publications

References 71 publications

Apolipoprotein B Secretion Is Regulated by Hepatic Triglyceride, and Not Insulin, in a Model of Increased Hepatic Insulin Signaling

Apolipoprotein B Secretion Is Regulated by Hepatic Triglyceride, and Not Insulin, in a Model of Increased Hepatic Insulin Signaling

Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance

Apolipoprotein B100 quality control and the regulation of hepatic very low density lipoprotein secretion

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