Role of PLIN2 in liver disease. (IMAGE)
Caption
(A) After HBx enters hepatocytes, mitochondrial ROS increases, which boosts PLIN2 expression, leading to the formation and accumulation of LDs through PPARα-RXRA and CREB-CREBBP pathways. Knockout of Abcb4 could inhibit PLIN2 expression and alleviate LD accumulation through the AMPK-CREB pathway. (B) In HCV-infected hepatocytes, higher PLIN2 levels increase the surface area of LD, providing a platform for more efficient HCV assembly. PLIN2 also promotes the total content of TAG and CE, aiding in the production of infectious viral particles, and increases HCV pseudo particle (HCVpp) entry and occludin expression. Inhibiting PLIN2 affects the transport of core and NS5A to the LD surface, hindering virus assembly initiation, and accelerates ApoE degradation by lysosomes, impacting virus assembly. (C) Alcohol can lead to CerS6 up-regulation, Setdb1 down-regulation, and compensatory down-regulation of miR-150 in cells. CerS6 up-regulation may enhance PLIN2 RNA stability, increase PLIN2 levels, promote LD formation, and promote alcoholic steatosis. Setdb1 down-regulation increases PLIN2 active transcription, inhibits AMPK phosphorylation, disrupts the formation of the CMA protein complex that captures PLIN2, stabilizes PLIN2 protein, and prevents LD degradation. miR-150 up-regulation could activate PLIN2 transcription and promote LD accumulation. (D) The increase in intracellular PLIN2 under HFD causes TAG and SE accumulation or promotes peroxisomal sequestration of unwanted or harmful lipids through oxidative chain reactions, leading to increased lipid peroxidation. Knockdown of PLIN2 could promote ATGL and autophagy to significantly increase FA oxidation. (E) PLIN2 increases in HCC cells, which inhibits the activity of the AMPK/ULK1 pathway, thereby delaying the degradation of HIF1α by lysosomes and promoting the proliferation of HCC cells. Trip13 expression increases in HCC cells, and inhibition of Trip13 can promote LD accumulation through the insulin receptor/Akt pathway. In the presence of PLIN2, through some unknown mechanism, LDs may convert into aMTOCs, destroy spindle polarity in mitosis, and lead to tumor cell death. Akt, protein kinase B; aMTOCs, acentric microtubule organizing centers; AMPK, adenosine monophosphate-activated protein kinase; Abcb4, ATP binding cassette subfamily B member 4; ApoE, apolipoprotein E; ATGL, adipose triacylglyceride lipase; CE, cholesteryl ester; CerS6, ceramide synthase 6; CMA, companion mediated autophagy; ER, endoplasmic reticulum; FA, fatty acid; HBx, hepatitis B virus X protein; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HFD, high-fat diet; HIF1α, hypoxia-inducible factor alpha; LDs, lipid droplets; PLIN2, perilipin 2; PPARγ, peroxisome proliferator-activated receptor γ; ROS, reactive oxygen species; SE, sterol ester; Setdb1, SET domain bifurcated 1; TAG, triacylglycerol; Trip13, thyroid hormone receptor factor 13; Ubr1, ubiquitin protein ligase E3 component n-recognin 1; ULK1, Unc-51-like autophagy-activating kinase 1; PPARα, peroxisome proliferator-activated receptor alpha; RXRA, retinoid X receptor alpha; CREB, cAMP-response element binding protein; CREBBP, CREB-binding protein.
Credit
Xuwen Xiang, Jing Chen, Lin Che
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