LXRs Regulate ER Stress and Inflammation through Dynamic Modulation of Membrane Phospholipid Composition

Rong, Xianglu; Albert, Carolyn J.; Hong, Cynthia; Duerr, Mark A.; Chamberlain, Brian T.; Tarling, Elizabeth J.; Ito, Ayaka; Gao, Jie; Wang, Bo; Edwards, Peter A.; Jung, Michael E.; Ford, David A.; Tontonoz, Peter

doi:10.1016/j.cmet.2013.10.002

Cited by 266 publications

(339 citation statements)

References 36 publications

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“…Acute knockdown of liver Lpcat3 in genetically obese mice exacerbates lipid-induced ER stress (8). However, the same group recently reported that Lpcat3 deficiency in the liver does not affect the expression of ER stress markers (9).…”

Section: Discussionmentioning

confidence: 97%

“…It has been reported that Lpcat3 protects against ER stress in the liver (8). To determine whether this also applies to the small …”

Section: Lpcat3 Deficiency Significantly Decreases Lipid Absorption Imentioning

confidence: 99%

“…Acute knockdown of Lpcat3 expression in the liver of genetically obese mice exacerbates lipid-induced endoplasmic reticulum (ER) stress (8). Moreover, global Lpcat3 knock-out (KO) mice exhibit neonatal lethality and have an abnormal small intestine (9,10).…”

mentioning

confidence: 99%

“…Lpcat3 is one of the downstream targets of liver X receptor (8) and peroxisome proliferator-activated receptor ␣ (6). Acute knockdown of Lpcat3 expression in the liver of genetically obese mice exacerbates lipid-induced endoplasmic reticulum (ER) stress (8).…”

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confidence: 99%

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Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Kabir

Bui

et al. 2016

Journal of Biological Chemistry

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Lysophosphatidylcholine acyltransferase 3 (Lpcat3) is involved in phosphatidylcholine remodeling in the small intestine and liver. We investigated lipid metabolism in inducible intestine-specific and liver-specific Lpcat3 gene knock-out mice. We produced Lpcat3-Flox/villin-Cre-ER T2 mice, which were treated with tamoxifen (at days 1, 3, 5, and 7), to delete Lpcat3 specifically in the small intestine. At day 9 after the treatment, we found that Lpcat3 deficiency in enterocytes significantly reduced polyunsaturated phosphatidylcholines in the enterocyte plasma membrane and reduced Niemann-Pick C1-like 1 (NPC1L1), CD36, ATP-binding cassette transporter 1 (ABCA1), and ABCG8 levels on the membrane, thus significantly reducing lipid absorption, cholesterol secretion through apoB-dependent and apoB-independent pathways, and plasma triglyceride, cholesterol, and phospholipid levels, as well as body weight. Moreover, Lpcat3 deficiency does not cause significant lipid accumulation in the small intestine. We also utilized adenovirus-associated virus-Cre to deplete Lpcat3 in the liver. We found that liver deficiency only reduces plasma triglyceride levels but not other lipid levels. Furthermore, there is no significant lipid accumulation in the liver. Importantly, small intestine Lpcat3 deficiency has a much bigger effect on plasma lipid levels than that of liver deficiency. Thus, inhibition of small intestine Lpcat3 might constitute a novel approach for treating hyperlipidemia.The majority of lipids on the cell membrane as well as the plasma lipoproteins are phospholipids, in particular phosphatidylcholines (PCs) 2 (1, 2). Monounsaturated and saturated fatty acids are usually esterified at the sn-1 position of PCs, whereas polyunsaturated fatty acids are esterified at the sn-2 position (3). The asymmetric distribution of fatty acids at the sn-1 and sn-2 positions of PCs is maintained in part by a deacylationreacylation process known as the Lands cycle or PC remodeling (3, 4). One key enzyme in this remodeling is lysophosphatidylcholine acyltransferase (Lpcat), which utilizes lyso-PC and polyunsaturated acyl-CoA to produce sn-2 polyunsaturated PCs. There are four isoforms of this enzyme (5), and Lpcat3 is the major isoform in the small intestine and liver (6 -8).Lpcat3 is one of the downstream targets of liver X receptor (8) and peroxisome proliferator-activated receptor ␣ (6). Acute knockdown of Lpcat3 expression in the liver of genetically obese mice exacerbates lipid-induced endoplasmic reticulum (ER) stress (8). Moreover, global Lpcat3 knock-out (KO) mice exhibit neonatal lethality and have an abnormal small intestine (9, 10). Liver-specific deletion of Lpcat3 has no effect on ER stress but results in a reduction of plasma triglycerides and induction of hepatosteatosis under high fat feeding conditions (9). Because of neonatal lethality (non-inducible approach was utilized), only 1-week-old newborns were analyzed for the impact of intestine-specific Lpcat3 deficiency on lipid metabolism (9). Very recently, we found that...

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Section: Discussionmentioning

confidence: 97%

“…It has been reported that Lpcat3 protects against ER stress in the liver (8). To determine whether this also applies to the small …”

Section: Lpcat3 Deficiency Significantly Decreases Lipid Absorption Imentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Kabir

Bui

et al. 2016

Journal of Biological Chemistry

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“…According to a recent study, LXR signaling is indeed involved in the dynamic modulation of membrane lipid composition by promoting the incorporation of unsaturated fatty acids into phospholipids in response to changes in cellular lipid metabolism. This LXR-mediated phospholipid remodeling might affect the biophysical characteristics of biological membranes and thus might also be involved in the modification of transmembrane protein function (Rong et al, 2013). …”

Section: Au6mentioning

confidence: 99%

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

Hegedüs

Telbisz

Hegedüs

et al. 2015

Advances in Cancer Research

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Liver X receptors link lipid metabolism and inflammation

2017

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The response of immune cells to pathogens is often associated with changes in the flux through basic metabolic pathways. Indeed, in many cases changes in metabolism appear to be necessary for a robust immune response. The Liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that regulate gene networks controlling cholesterol and lipid metabolism. In immune cells, particularly in macrophages, LXRs also inhibit pro-inflammatory gene expression. This Review will highlight recent studies that connect LXR-dependent control of lipid metabolism to regulation of the immune response.

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LXRs Regulate ER Stress and Inflammation through Dynamic Modulation of Membrane Phospholipid Composition

Cited by 266 publications

References 36 publications

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

Liver X receptors link lipid metabolism and inflammation

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