Opposing roles of cell death-inducing DFF45-like effector B and perilipin 2 in controlling hepatic VLDL lipidation

Abstract

triglycerides (TAG) and cholesterol and for the development of metabolic disorders, including obesity, diabetes, and hepatic steatosis. It is believed that VLDL assembly and maturation involves two steps ( 1, 2 ). The fi rst step is the formation of lipid-poor pre-VLDL particles involving the cotranslational lipidation of apolipoprotein B (apoB) with a few lipids, aided by microsomal triglyceride transfer protein (MTP) ( 3, 4 ). The second step is the transfer of large quantities of lipids, likely from TAG-rich lipid droplets (LD), to the pre-VLDL particles, converting the pre-VLDL particles into lipid-rich, mature VLDL particles ( 2-5 ). Thus far, the subcellular site of the addition of bulk lipids to pre-VLDL particles, the source of the lipids, and the factors promoting VLDL lipidation remain unclear. The endoplasmic reticulum (ER) has been suggested as the VLDL lipidation site because the majority of TAG is synthesized in the ER, and apoB-100 has been shown to be localized to the ER membrane ( 2, 6, 7 ). Others believe that the pre-VLDL particles are assembled in the ER and then exit, with the fi nal VLDL lipidation and maturation occurring primarily within the Golgi apparatus or post-ER compartments ( 8-11 ). For example, the biochemical separation of the lipoprotein particles from McA-RH7777 cells indicated that mature VLDL particles accumulate in the Golgi but not in the ER fractions ( 11,12 ). In addition, the late addition of bulk lipids to pre-VLDL particles is independent of both MTP activity and new triglyceride synthesis ( 12, 13 ).The availability of neutral lipids and the capacity to transfer TAG to pre-VLDL particles are crucial for VLDL lipidation and maturation. The LD, a subcellular organelle, Abstract Regulation of hepatic very low density lipoprotein (VLDL) assembly and maturation is crucial in controlling lipid homeostasis and in the development of metabolic disorders, including obesity, hepatic steatosis, and insulin resistance. Cideb, a member of cell death-inducing DFF45-like effector (CIDE) protein family, has been previously shown to promote VLDL lipidation and maturation. However, the precise subcellular location of Cideb-mediated VLDL lipidation and the factors modulating its activity remain elusive. In addition to its localization to endoplasmic reticulum (ER) and lipid droplets (LD), we observed that Cideb was also localized to the Golgi apparatus. Mature and lipid-rich VLDL particles did not accumulate in the Golgi apparatus in Cideb ؊ / ؊ livers. Interestingly, we observed that hepatic perilipin 2/adipose differentiation-related protein (ADRP) levels were markedly increased in Cideb ؊ / ؊ mice. Liver-specifi c knockdown of perilipin 2 in Cideb ؊ / ؊ mice resulted in the reduced accumulation of hepatic triglycerides (TAG), increased VLDL-TAG secretion, and the accumulation of mature TAG-rich VLDL in the Golgi apparatus. These data reveal that Cideb and perilipin 2 play opposing roles in controlling VLDL lipidation and hepatic lipid homeostasis. China,

Roles of Acyl-CoA:Diacylglycerol Acyltransferases 1 and 2 in Triacylglycerol Synthesis and Secretion in Primary Hepatocytes

“…This is perhaps not surprising because the capacity of triacylglycerol storage within the ER bilayer is limited, and triacylglycerol stored in cytosolic and ER lumenal depots is intimately linked. 37,[40][41][42][43] We next addressed whether inactivation of DGATs directly influences triacylglycerol use using an experimental protocol shown in Figure 5A. After the chase period, radioactivity in acid soluble metabolites and medium triacylglycerol was measured, which indicated FA oxidation and VLDL secretion, respectively.…”

CideB Protein Is Required for the Biogenesis of Very Low Density Lipoprotein (VLDL) Transport Vesicle

“…3 H]triacylglycerol (TAG) was prepared from rat liver using the same method as we have described previously (21 50 mM EDTA, and protease inhibitor (Roche Diagnostics GmbH, Mannheim, Germany) in a Parr bomb at 1,100 psi for 40 min followed by isolation of ER and cis-and trans-Golgi in a sucrose step gradient (21,42,56).…”

“…Of several important proteins, which are not present in other ER-derived vesicles such as PCTV and PTV, one protein was identified as CideB (cell death-inducing DFF45-like effector b) (48). Interestingly, CideB has been shown to be involved in secretion of VLDL (49,50). CideB belongs to the CIDE family, which includes CideA, CideB, and CideC, also called as Fsp27 in mice, and these proteins are reported to play important roles in lipoprotein metabolism (51).…”

Role of Lipid Droplet Proteins in the Development of NAFLD and Hepatic Insulin Resistance

“…CIDEA expression is controlled by SREBP-1c and found in a faty liver [41,42]. CIDEB is constitutively expressed in a liver and plays a role in VLDL production [43,44]. Interestingly, it has been reported that CIDEB and PLIN2 exert opposite functions for a control of VLDL lipidation [44].…”

“…CIDEB is constitutively expressed in a liver and plays a role in VLDL production [43,44]. Interestingly, it has been reported that CIDEB and PLIN2 exert opposite functions for a control of VLDL lipidation [44]. CIDEC, is also named as fat-speciic protein 27 (FSP27), found as a cofactor of PLIN1 for lipid droplet fusion in adipocytes [15].…”