Impaired VLDL secretion following Mttp deletion promotes tumorigenesis and is accelerated by Fabp1 deletion
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1066795 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27663346.fastq.gz | Fastqsanger.gz | |||
| SRR27663347.fastq.gz | Fastqsanger.gz | |||
| SRR27663348.fastq.gz | Fastqsanger.gz | |||
| SRR27663349.fastq.gz | Fastqsanger.gz | |||
| SRR27663350.fastq.gz | Fastqsanger.gz |
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Project description:Genetic polymorphisms that impair VLDL secretion are linked to hepatic steatosis, fibrosis and hepatocellular cancer (HCC). Liver-specific deletion of microsomal triglyceride transfer protein (Mttp-LKO) impairs VLDL assembly, promoting hepatic steatosis and fibrosis, which are attenuated in Mttp-LKO mice with germline Fabp1 deletion (Fabp1/Mttp DKO) mice. Here we examine the impact of impaired VLDL secretion in Mttp-LKO mice on HCC incidence and progression in comparison to Fabp1/Mttp DKO mice. DEN treated Mttp-LKO mice exhibited steatosis with increased tumor burden compared to flox controls, while diethylnitrosamine (DEN)- treated Fabp1/Mttp DKO mice exhibited a paradoxical increase in tumor burden and >50% mortality by 50 weeks. Lipidomic surveys revealed progressive enrichment in distinct triglyceride species in livers from Mttp-LKO mice with further enrichment in Fabp1/Mttp DKO mice. RNAseq analysis performed on liver tissue at 6 months revealed mRNA changes suggesting altered monocarboxylic acid utilization and increased aerobic glycolysis, while hepatocytes from Fabp1/Mttp DKO mice exhibited increased capacity to utilize glucose and glutamine. Taken together, these findings demonstrate that hepatic tumorigenesis is increased in mice with impaired VLDL secretion and further accelerated via pathways including altered fatty acid compartmentalization and shifts in hepatic energy utilization.
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Project description:We’ve previously demonstrated that hepatocytes with Tbx3 deletions have increased cellular fitness and clonally expand during metabolic-dysfunction associated steatotic liver disease (MASLD) development. TBX3 is a transcription factor that is critical for embryonic development, but has never been studied within the context of MASLD. Here, we show that somatic mutations in TBX3 are found in human patients with MASLD. Liver specific deletion of Tbx3 in mice protects against diet induced MASLD through upregulating VLDL-TG particle secretion. TBX3 transcriptionally suppresses the conventional secretory pathway and cholesterol biosynthesis. Hdlbp is a direct target of TBX3 that is responsible for altered VLDL secretion. In contrast to WT TBX3, TBX3 harboring somatic mutations found in humans failed to suppress VLDL secretion in vivo. In conclusion, mutations in TBX3 promote clonal expansion during MASLD development through increased lipid disposal, demonstrating clonal fitness can benefit the liver even at the cost of hyperlipidemia.
2025-06-30 | GSE300981 | GEO
Project description:Hepatic very low-density lipoprotein (VLDL) is essential for maintaining lipid metabolism in the liver. Sphingosine kinases (SphKs) are essential rate-limiting enzymes that catalyze sphingosine phosphorylation to Sphingosine-1-phosphate (S1P). SphKs exist as two isoforms, SphK1 and SphK2, both highly expressed in the liver. SphK1 plays a critical role in regulating hepatic inflammation and drug metabolism. This study aimed to determine whether SphK2 regulates hepatic lipid metabolism, particularly VLDL secretion. Immunohistochemical staining revealed decreased SphK2 protein levels within regions proximal to hepatic lipid accumulation in individuals diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD). Sphk2−/− mice exhibited spontaneous hepatocyte lipid accumulation and reduced VLDL secretion. Proteomic analysis revealed that SphK2 deficiency impaired soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) complex interactions involved in vesicular transport and organelle membrane fusion. Furthermore, SphK2 deficiency results in accelerated degradation of the SEC22B, STX5A, and GS28 proteins via chaperone-mediated autophagy (CMA), impeding VLDL transport to the Golgi apparatus. MYH1485, a specific activator of mTOR, induces mTORC2 phosphorylation, thereby inhibiting the degradation of SNARE complexes by CMA and counteracting the lipid accumulation induced by SphK2 deficiency. Exogenous S1P supplementation markedly reversed the reduction in mTORC2 phosphorylation and suppressed CMA, thereby improving VLDL secretion. Our study elucidates an inventive regulatory mechanism by which SphK2 modulates CMA by activating mTORC2 phosphorylation, promoting VLDL secretion, and balancing lipid metabolism in the liver. These findings provide insights into SphK2 function and the underlying mechanisms involved in the regulation of VLDL secretion, which may facilitate MASLD treatment.
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Project description:The PPAR? activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced VLDL-TG clearance and decreased VLDL-TG production. However, since data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%; P<0.001) and TG (-60%; P<0.001) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (-68%; P<0.01). This was associated with an increased post-heparin LPL activity (+110%; P<0.0001) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%; P<0.0001) but not the VLDL-apoB production rate. Kinetic studies using [3H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma FA and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. After 4 hours fasting, livers were isolated and individual gene arrays were performed.
2010-05-27 | E-GEOD-21211 | biostudies-arrayexpress
Project description:Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion
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Project description:The PPARα activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced VLDL-TG clearance and decreased VLDL-TG production. However, since data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%; P<0.001) and TG (-60%; P<0.001) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (-68%; P<0.01). This was associated with an increased post-heparin LPL activity (+110%; P<0.0001) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%; P<0.0001) but not the VLDL-apoB production rate. Kinetic studies using [3H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma FA and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver.
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Project description:The liver exerts a wide range of essential functions including the synthesis of plasma proteins and the integration of glucose and lipid homeostasis. While the role of transcriptional networks in the tight regulation of these processes has been extensively studied in healthy and disease states, much less is known about post-transcriptional control of gene expression through RNA-binding proteins (RBP). Here, we report that the highly expressed and conserved RBP Hdlbp/Vigilin is upregulated in patients with non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) and in livers of insulin resistant obese mice. Gain and loss of function studies revealed that Vigilin regulates VLDL secretion through the modulation of ApoB mRNA translation. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) analysis in primary hepatocytes demonstrated that Vigilin predominantly binds to CU-rich regions in coding sequences of transcripts of further metabolically relevant secretory proteins such as Apob/apoliproteinB, Ahsg/fetuin-A, Apoc3/apolipoproteinC-III, Fn1/fibronectin, Orm1/orosomucoid and Serpina1/alpha-1-antitrypsin. While mRNA levels of these targets did not change, protein levels were substantially decreased upon knockdown of Vigilin. Hepatic long-term knockdown via GalNAc-conjugated siRNAs ameliorated elevated VLDL/LDL levels and the formation of atherosclerotic plaques in Ldlr–/– mice. These studies uncover a role for Vigilin as a key regulator of hepatic Apob translation and secretion through binding to its mRNA and demonstrate the therapeutic potential of inhibiting Vigilin for cardiovascular diseases.
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