title: A regulator of secretory vesicle size, Kelch-like protein 12, facilitates the secretion of apolipoprotein B100 and very-low-density lipoproteins--brief report.
abstract: OBJECTIVE
  One of the major risk factors for atherosclerosis is the plasma level of low-density lipoprotein (LDL), which is a product of very-low-density lipoprotein (VLDL). Hepatic apolipoprotein B100 (apoB100) is the essential component that provides structural stability to VLDL particles. Newly translated apoB100 is partially lipidated in the endoplasmic reticulum (ER), forming nascent apoB100-VLDL particles. These particles are further modified to form fully mature VLDLs in the Golgi apparatus. Therefore, the transport of nascent VLDL from the ER to the Golgi represents a critical step during VLDL maturation and secretion and in regulating serum LDL cholesterol levels. Our previous studies showed that apoB100 exits the ER in coat complex II vesicles (COPII), but the cohort of related factors that control trafficking is poorly defined.
  
  
  RESULTS
  Expression levels of Kelch-like protein 12 (KLHL12), an adaptor protein known to assist COPII-dependent transport of procollagen, were manipulated by using a KLHL12-specific small interfering RNA and a KLHL12 expression plasmid in the rat hepatoma cell line, McArdle RH7777. KLHL12 knockdown decreased the secreted and intracellular pools of apoB100, an effect that was attenuated in the presence of an autophagy inhibitor. KLHL12 knockdown also significantly reduced secretion of the most lipidated apoB100-VLDL species and led to the accumulation of apoB100 in the ER. Consistent with these data, KLHL12 overexpression increased apoB100 recovery and apoB100-VLDL secretion. Images obtained from confocal microscopy revealed colocalization of apoB100 and KLHL12, further supporting a direct link between KLHL12 function and VLDL trafficking from the ER.
  
  
  CONCLUSIONS
  KLHL12 plays a critical role in facilitating the ER exit and secretion of apoB100-VLDL particles, suggesting that KLHL12 modulation would influence plasma lipid levels.
authors: From the Department of Medicine, Leon H. Charney Division of Cardiology, Department of Cell Biology, and the Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine (C.B., L.G., B.R., A.W., K.J.M., E.A.F.); and Department of Biological Sciences, University of Pittsburgh, PA (J.L.B.). C.B. is currently affiliated with Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada.
authors: Chutikarn
authors: C
authors: Butkinaree
authors: Liang
authors: L
authors: Guo
authors: Bhama
authors: B
authors: Ramkhelawon
authors: Amarylis
authors: A
authors: Wanschel
authors: Jeffrey L
authors: JL
authors: Brodsky
authors: Kathryn J
authors: KJ
authors: Moore
authors: Edward A
authors: EA
authors: Fisher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism*; D022181:COP-Coated Vesicles / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference; D051381:Rats; D022142:Secretory Vesicles / Q000378:metabolism*; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053299:Apolipoprotein B-100; C493279:KLHL12 protein, human; D008079:Lipoproteins, VLDL; D008840:Microfilament Proteins
keywords: COP-coated vesicles; KLHL12; apolipoproteins B; lipoproteins, VLDL