3, 4 In lipid-poor conditions or in the absence of microsomal tri

3, 4 In lipid-poor conditions or in the absence of microsomal triglyceride transfer protein activity, a large proportion of newly synthesized apoB is

rapidly ubiquitinated and degraded Palbociclib by the proteasome.5 ERAD has also been implicated in apoB degradation in primary hepatocytes, which were shown to ubiquitinate and degrade apoB via the proteasome, although at much lower rate compared to HepG2 cells.6 Experimental evidence has also suggested that N-terminal cleavage of nascent apoB is another mechanism involved in the proteolysis of apoB within the ER lumen. Using a permeabilized cell system, we reported the existence of a nonproteasomal degradative pathway that is responsible for specific fragmentation of apoB and generation

of a 70-kDa fragment.7 Permeabilized cells, selleck compound largely devoid of the cytosolic proteasome components, continued to degrade apoB and generated specific fragments, including a 70-kDa fragment, via a lactacystin-insensitive process.8 This observation was supported by Du et al. who demonstrated that an N-terminus of 85-kDa apoB fragment was generated in microsomes following transient overexpression of human apoB53 in CHO (Chinese hamster ovary) cells.9 Studies with LDL receptor–deficient hepatocytes (Ldlr−/−) have revealed that LDL receptor plays a critical role in the degradation of newly synthesized apoB.10 Twisk et al.10 reported that LDL receptor–deficient hepatocytes (Ldlr−/−) secreted more apoB compared to wild-type (WT) hepatocytes, due to reduced degradation of newly synthesized apoB in Ldlr−/− hepatocytes. Recently, more evidence has been obtained showing that apoB turnover is associated with the levels of the LDL receptor. Growing evidence also suggests that autophagy, a late-stage protein quality control system, can mediate apoB degradation.11-13 Autophagy is a degradation process for

cellular components in which double-membrane autophagosomes sequester organelles or portions of cytosol and fuse with lysosomes or vacuoles to facilitate breakdown by resident hydrolases.14 Ohsaki et al. first observed selleck colocalization of proteasomes, autophagosomes, and apoB in a structure containing lipid droplets, suggesting the involvement of an autophagic mechanism in apoB degradation.11 Soon after, Pan et al. showed that autophagic degradation of apoB occurred via post-ER presecretory proteolysis, induced by reactive oxygen species generated within hepatocytes from dietary polyunsaturated fatty acids.12 More recently, Yao and colleagues demonstrated autophagic degradation of an apoB mutant (Ala31Pro substitution), which led to decreased secretion of endogenous apoB and triglycerides.13 Thus ample evidence now exists for apoB autophagy, although the molecular mechanisms involved in targeting apoB to intracellular autophagy are currently unknown.

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