Fasting Induces Hyperlipidemia in Mice Overexpressing Proprotein Convertase Subtilisin Kexin Type 9: Lack of Modulation of Very-Low-Density Lipoprotein Hepatic Output by the Low-Density Lipoprotein Receptor

Abstract

Several proprotein convertase subtilisin kexin type 9 (PCSK9) mutations lead to familial hypercholesterolemia by virtue of its role as a negative modulator of the low-density lipoprotein receptor (LDLr). Here, we uncover that upon dietary challenge, the down-regulation of the LDLr is also a key mechanism by which PCSK9 modulates the hepatic production of apolipoprotein-B-containing lipoproteins. Thus, adenoviral-mediated overexpression of PCSK9 in 24-h fasted mice results in massive hyperlipidemia, due to a striking increase in very-low-density lipoprotein (VLDL) triglycerides and apolipoprotein B100 hepatic output. Similar studies in LDLr (-/-) mice demonstrate that PCSK9-mediated alteration of VLDL output in the fasted state requires the LDLr. This increased production of VLDL was associated with a concomitant reduction of intrahepatic lipid stores as well as a lack of down-regulation of peroxisome proliferator-activated receptor-alpha activity and target genes expression. Finally, we show that PCSK9 hepatic expression is inhibited by the hypotriglyceridemic peroxisome proliferator-activated receptor-alpha agonist fenofibrate. In summary, the negative modulation of LDLr expression by PCSK9, which decreases plasma LDL clearance, also promotes an overproduction of nascent VLDL in vivo upon fasting.

Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice

“…For the in vivo pioglitazone treatment, mice were fed with chow diet (Safe, Augy, France) supplemented with pioglitazone (Actos; Takeda, Puteaux, France) at a concentration of 300 mg/kg (45 mg kg −1 day −1 ). [17].…”

“…We measured VLDL-TAG secretion rate using the lipoprotein lipase inhibitor tyloxapol, which blocks TAG clearance from the bloodstream [17]. As shown in Fig.…”

Correlation between liver cancer occurrence and gene expression profiles in rat liver tissue

“…However, some important genes involved in glycolysis and gluconeogenesis, such as pfkfb4 regulating the level of fructose 2, 6-bisphosphate, pyruvate kinase pklr, sds (Ogawa et al, 2002) and g6pc promoting gluconeogenesis, onecut1 inducing gene expression of glucose kinase and glucose-6-phosphase (Lannoy et al, 2002;Beaudry et al, 2006), and nuclear transcription factors ppargc1a, ppp1r3c and ppp1r3b, were downregulated, which possibly could explain why the synergy values of carbohydrate metabolismrelated genes were was significantly smaller than E c of the control at the period of 8-18w. As for lipid metabolism-related genes, mogat2 catalyzing monoacylglycerol into 1, 2-diacylglycerol, apoa5 and ldlr promoting triacylglycerol transport and storage, pcsk9 negatively regulating the storage of triacylglycerols (Lambert et al, 2006), cpt1a promoting fatty acid oxidation, elovl5 specific for very long chain fatty acid elongation, cyp7a1 in bile acid synthesis, nuclear receptor nr5a2 inhibiting bile acid synthesis, hsd3b5 and sult1e1 catalyzing cholesterol into sex hormone, akr1c18 and akr1c1 in steroid hormone metabolism, and multiple genes within the pathway of cholesterol synthesis, including 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (hmgcs1), isopentenyl-diphosphate delta isomerase (idi1), sterol C4 methyl oxidaselike (sc4mol), and abcg8 involved in cholesterol efflux, were attenuated with the expression bottom mainly at 12-18w. It was not contrary to the fact that lipid metabolism was decreased at 5-18w of LC by gene synergy analysis.…”

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): Lessons Learned from Patients with Hypercholesterolemia

“…Hepatic ligand-activated receptors, including the farnesoid X receptor, PPAR (peroxisome proliferatoractivated receptor), and HNF1 (hepatocyte nuclear factor 1) regulate PCSK9 transcription (21 ). The physiological significance of these regulatory pathways is unknown.…”