A novel multiprotein complex is required to generate the prechylomicron transport vesicle from intestinal ER

Siddiqi, Shadab A.; Saleem, Umair; Abumrad, Nada A.; Davidson, Nicholas O.; Storch, Judith; Mansbach, Charles M.

doi:10.1194/jlr.m005611

Cited by 92 publications

(104 citation statements)

References 52 publications

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“…Because the reduction in intestinal TG secretion in caspase-1 Ϫ / Ϫ mice cannot be explained by a reduction of lipid availability within the enterocytes, it may be caused by a reduction in intracellular transport of lipids. We observed a decreased intestinal expression of L-FABP in caspase-1 Ϫ / Ϫ mice, a protein that is involved in the activation and transport of FA toward the ER, as well as budding of prechylomicron transport vesicles ( 21,25 ). Because L-FABP-defi cient mice display a reduction in intestinal lipid traffi cking ( 20 ), it is conceivable that a reduced L-FABP expression limits chylomicron secretion, provided that a reduced expression of L-FABP affected the uptake and adipogenesis; rather, data from the current study show that caspase-1 defi ciency reduces TG-derived FA delivery to the adipose tissue secondary to a reduction in TG-rich lipoprotein secretion.…”

Section: Discussionmentioning

confidence: 92%

Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion

Diepen

Stienstra

Vroegrijk

et al. 2013

Journal of Lipid Research

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Obesity is accompanied by low-grade chronic systemic infl ammation characterized by increased circulating levels of proinfl ammatory cytokines, including interleukin (IL)-1 ␤ , tumor necrosis factor (TNF)-␣ , and IL-6 ( 1 ). Activation of infl ammatory pathways induces metabolic disturbances, leading to insulin resistance, dyslipidemia, and cardiovascular diseases. Caspase-1 is a cysteine protease that is known for its crucial role in the activation of the proinfl ammatory cytokines IL-18 and IL-1 ␤ . Additionally, caspase-1 has been shown to cleave other substrates, including proteins involved in energy metabolism ( 2-4 ). Caspase-1 activation is controlled by the infl ammasome, a multiprotein Abstract Caspase-1 is known to activate the proinfl ammatory cytokines IL-1 ␤ and IL-18. Additionally, it can cleave other substrates, including proteins involved in metabolism. Recently, we showed that caspase-1 defi ciency in mice strongly reduces high-fat diet-induced weight gain, at least partly caused by an increased energy production. Increased feces secretion by caspase-1-defi cient mice suggests that lipid malabsorption possibly further reduces adipose tissue mass. In this study we investigated whether caspase-1 plays a role in triglyceride-(TG)-rich lipoprotein metabolism using caspase-1-defi cient and wild-type mice. Caspase-1 defi ciency reduced the postprandial TG response to an oral lipid load, whereas TG-derived fatty acid (FA) uptake by peripheral tissues was not affected, demonstrated by unaltered kinetics of [ Lipid composition of fecesMice were individually housed for 4 days to determine food intake and collect feces quantitatively. Feces were weighed, freeze-dried, and ground, and fecal fatty acids (FA) were derivatized by methyl esterifi cation. Therefore, 2 ml methanol/hexane (4:1 v/v) containing 80 µg pentadecanoic acid (C15:0) as an internal standard (Fluka) was added to 15 mg of feces. Then, 200 µL acetyl chloride (Merck) was added, and samples were incubated at 95°C. After cooling to 4°C, 5 ml 6% K 2 CO 3 (Sigma) was added, and samples were centrifuged (10 min; 4,000 rpm, 4°C). The upper hexane layer was isolated and used for GC analysis of FA methyl esters (FAME). FAME were separated on a 50 m × 0.25 mm capillary GC column (CP Sil 88; Agilent technologies) in a 3800 GC gas chromatograph (Varian) equipped with a fl ame ionization detector. The injector and fl ame ionization detector were kept at 270°C. The column temperature was programmed from 170°C to 210°C. FAME were introduced by split injection (split ratio 20:1). Quantifi cation was based on the area ratio of the individual FA to the internal standard.To extract total cholesterol from feces, dried feces (10 mg) were incubated in 1 ml alkaline methanol (CH 3 OH: 1 M NaOH = 3:1 [v/v]) for 2 h at 80°C in screw-capped tubes using 5 ␣ -cholestane as internal standard. Tubes were cooled to room temperature, and the cholesterol was extracted twice with 2 ml petroleum ether. The combined petroleum ether layers were evaporated to dryness, and the ...

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Section: Discussionmentioning

confidence: 92%

Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion

Diepen

Stienstra

Vroegrijk

et al. 2013

Journal of Lipid Research

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“…Thus CD36 expression in the liver might play dual roles: facilitating FA fl ux under conditions of high FA supply ( 11,12 ) and transducing intracellular signals that regulate phospholipid deacylation and eicosanoid production, events that would infl uence assembly and secretion of VLDL particles. Future studies will need to determine whether CD36 is part of the protein complex required for VLDL formation as has been documented in enterocytes during chylomicron production ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

CD36 deletion reduces VLDL secretion, modulates liver prostaglandins, and exacerbates hepatic steatosis in ob/ob mice

Nassir

Adewole

Brunt

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org novo FA synthesis or de novo lipogenesis (DNL), decreased FA oxidation, and reduced secretion of VLDLs ( 1, 2 ).CD36 is a class B scavenger receptor that plays an important role in several pathways of FA utilization. The protein is expressed in many cell types, including lingual taste bud cells, enterocytes, adipocytes, myocytes, and immune cells. On taste bud cells, CD36 is important for FA recognition and fat perception ( 3, 4 ). In skeletal muscle, heart, and adipose tissue, CD36 facilitates tissue FA uptake and utilization ( 5, 6 ). In the small intestine, it is important for chylomicron secretion ( 7 ) and for FA-induced release of secretin and cholecystokinin ( 8 ). In the liver, CD36 is expressed on endothelial, parenchymal, and Kupffer cells ( 9 ). Basal expression of liver CD36 is low but increases in experimental models of hepatic steatosis, such as genetic obesity and highfat feeding ( 10, 11 ) or following activation of the prosteatotic transcription factors liver X receptor (LXR), pregnane X receptor (PXR), and aryl hydrocarbon receptor (AHR) by xenobiotics, bacteria, or cytokines ( 12 ). Mice fed a highfat diet have increased liver CD36 expression associated with enhanced hepatic FA uptake and TG accumulation, and these are prevented by CD36 deletion ( 11 ). Interestingly, however, the prosteatotic effects of a high-fructose diet, which enhances DNL and TG accumulation in the liver ( 13 ), are exacerbated by CD36 deletion ( 14 ).In humans with nonalcoholic fatty liver disease (NAFLD), hepatic CD36 positively correlates with liver fat content ( 15 ), but its relationship to output of VLDL suggests that its impact on hepatic FA metabolism might not be limited to enhancing FA fl ux and TG accumulation. NAFLD is Abstract Recent findings described the role of CD36-mediated signaling in regulating cellular calcium and the release of various bioactive molecules, including the prostaglandins, neurotransmitters, cholecystokinin, and secretin. Here we document the role of CD36 in the secretion of hepatic VLDL. CD36 deletion resulted in 60% suppression of VLDL output in vivo, and VLDL secretion was reduced in vitro using incubated liver slices. The effect of CD36 deletion was mediated by enhancing formation of hepatic prostaglandins D2, F2, and E2. Treatment of CD36-defi cient slices with inhibitors of cyclooxygenases reversed the reduction in triglyceride secretion. We also examined the effect of CD36 deletion on the obesity-associated spontaneous steatosis of the ob/ob mouse that is driven by enhanced de novo lipogenesis. Homozygous ob/ob mice lacking CD36 ( ob-CD36 ؊ / ؊ ) were generated and studied for hepatic triglyceride accumulation and VLDL secretion. Livers of ob/ob mice were steatotic as expected and had 5-fold more CD36 on Kupffer cells and hepatocytes. CD36 deletion exacerbated the steatosis by impairing hepatic triglyceride and apoB secretion through increasing prostaglandin levels. These fi ndings suggest an unappreciated role of CD36 in reg...

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“…Once bound to Sar1b, it phosphorylates a threonine ( 7 ). The consequence of Sar1b phosphorylation is to free FABP1 from its cytosolic heterotetramer ( 7 ), enabling it to bind to the ER and organize the PCTV budding complex ( 4,6,7 ).…”

Section: Discussionmentioning

confidence: 99%

Dietary and biliary phosphatidylcholine activates PKCζ in rat intestine

Siddiqi

Mansbach

2015

Journal of Lipid Research

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A novel multiprotein complex is required to generate the prechylomicron transport vesicle from intestinal ER

Cited by 92 publications

References 52 publications

Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion

Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion

CD36 deletion reduces VLDL secretion, modulates liver prostaglandins, and exacerbates hepatic steatosis in ob/ob mice

Dietary and biliary phosphatidylcholine activates PKCζ in rat intestine

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