Dietary carbohydrates regulate hepatic lipogenesis by controlling the expression of critical enzymes in glycolytic and lipogenic pathways. Here we report that the transcription factor XBP1, a key regulator of the Unfolded Protein Response (UPR), is required for the unrelated function of normal fatty acid synthesis in the liver. XBP1 protein expression is induced in the liver by a high carbohydrate diet and directly controls the induction of critical genes involved in fatty acid synthesis. Inducible, selective deletion of XBP1 in liver resulted in marked hypocholesterolemia and hypotriglyceridemia, secondary to a decreased production of lipids from the liver. This phenotype was not accompanied by hepatic steatosis or significant compromise in protein secretory function. The discovery of XBP1 as a regulator of lipogenesis has important implications for human dyslipidemias.Hepatic lipid synthesis increases upon ingestion of carbohydrates, which may be converted into triglyceride (TG) in the liver and transported to adipose tissue for energy storage. Dysregulation of hepatic lipid metabolism is closely related to the development of metabolic syndrome, a condition characterized by the constellation of central obesity, dyslipidemia, elevated blood glucose and hypertension (1). In mammals, hepatic lipid metabolism is controlled by transcription factors, such as liver X receptor (LXR), sterol regulatory element-binding proteins (SREBPs) and ChREBP that regulate the expression of critical enzymes involved in glycolytic and lipogenic pathways (2).XBP1 is a key regulator of the mammalian unfolded protein response (UPR) or endoplasmic reticulum (ER) stress response (3). Upon ER stress, the proximal sensor and endoribonuclease IRE1α induces unconventional splicing of XBP1 mRNA to generate a mature mRNA encoding an active transcription factor, XBP1s, which directly binds to the promoter region of ER chaperone genes (4-6). Mice lacking XBP1 display severe abnormalities in the development and function of professional secretory cells, such as 4 Corresponding authors:
Insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial. Liver insulin receptor knockout (LIRKO) mice have pure hepatic insulin resistance. On a standard chow diet, LIRKO mice have a proatherogenic lipoprotein profile with reduced high-density lipoprotein (HDL) cholesterol and very low-density lipoprotein (VLDL) particles that are markedly enriched in cholesterol. This is due to increased secretion and decreased clearance of apolipoprotein B-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of Pgc-1 beta (Ppargc-1b), which promotes VLDL secretion, but decreased expression of Srebp-1c (Srebf1), Srebp-2 (Srebf2), and their targets, the lipogenic enzymes and the LDL receptor. Within 12 weeks on an atherogenic diet, LIRKO mice show marked hypercholesterolemia, and 100% of LIRKO mice, but 0% of controls, develop severe atherosclerosis. Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome.
The Star (steroidogenic acute regulatory protein)-related transfer (START) domain superfamily is characterized by a distinctive lipid-binding motif. START domains typically reside in multidomain proteins, suggesting their function as lipid sensors that trigger biological activities. Phosphatidylcholine transfer protein (PC-TP, also known as StarD2) is an example of a START domain minimal protein that consists only of the lipidbinding motif. PC-TP, which binds phosphatidylcholine exclusively, is expressed during embryonic development and in several tissues of the adult mouse, including liver. Although it catalyzes the intermembrane exchange of phosphatidylcholines in vitro, this activity does not appear to explain the various metabolic alterations observed in mice lacking PC-TP. Here we demonstrate that PC-TP function may be mediated via interacting proteins. Yeast two-hybrid screening using libraries prepared from mouse liver and embryo identified Them2 (thioesterase superfamily member 2) and the homeodomain transcription factor Pax3 (paired box gene 3), respectively, as PC-TP-interacting proteins. These were notable because the START domain superfamily contains multidomain proteins in which the START domain coexists with thioesterase domains in mammals and with homeodomain transcription factors in plants. Interactions were verified in pulldown assays, and colocalization with PC-TP was confirmed within tissues and intracellularly. The acyl-CoA thioesterase activity of purified recombinant Them2 was markedly enhanced by recombinant PC-TP. In tissue culture, PC-TP coactivated the transcriptional activity of Pax3. These findings suggest that PC-TP functions as a phosphatidylcholine-sensing molecule that engages in diverse regulatory activities that depend upon the cellular expression of distinct interacting proteins. Phosphatidylcholine transfer protein (PC-TP)5 is a soluble lipid-binding protein with high specificity for phosphatidylcholines (1, 2). Whereas PC-TP promotes intermembrane exchange of phosphatidylcholines in vitro, its physiological function in vivo is not well understood (3). Studies in tissue culture and knock-out mice have demonstrated physiological roles for PC-TP in hepatobiliary lipid homeostasis, reverse cholesterol transport, and high density lipoprotein metabolism (3). However, these effects do not appear to be fully explained by the phosphatidylcholine transfer activity of PC-TP.PC-TP (also known as StarD2) is a member of a steroidogenic acute regulatory protein-related transfer (START) domain protein superfamily (4). START domains are conserved motifs that bind hydrophobic ligands. Proteins that contain START domains participate in intracellular lipid transport, lipid metabolism, and cellular signaling (5-7). START domain proteins are expressed from bacteria to higher organisms but are most numerous in plants (8).START domains largely reside within multidomain proteins, suggesting that binding of a hydrophobic ligand might regulate activity of another domain within the same protein. By cont...
Phosphatidylcholine transfer protein (PC-TP, also known as StarD2) is a highly specific intracellular lipid binding protein with accentuated expression in oxidative tissues. Here we show that decreased plasma concentrations of glucose and free fatty acids in fasting PC-TP-deficient (Pctp(-/-)) mice are attributable to increased hepatic insulin sensitivity. In hyperinsulinemic-euglycemic clamp studies, Pctp(-/-) mice exhibited profound reductions in hepatic glucose production, gluconeogenesis, glycogenolysis, and glucose cycling. These changes were explained in part by the lack of PC-TP expression in liver per se and in part by marked alterations in body fat composition. Reduced respiratory quotients in Pctp(-/-) mice were indicative of preferential fatty acid utilization for energy production in oxidative tissues. In the setting of decreased hepatic fatty acid synthesis, increased clearance rates of dietary triglycerides and increased hepatic triglyceride production rates reflected higher turnover in Pctp(-/-) mice. Collectively, these data support a key biological role for PC-TP in the regulation of energy substrate utilization.
Phosphatidylcholine transfer protein (PC-TP) is a highly specific soluble lipid binding protein that transfers phosphatidylcholine between membranes in vitro. PC-TP is a member of the steroidogenic acute regulatory protein-related transfer (START) domain superfamily. Although its biochemical properties and structure are well characterized, the functions of PC-TP in vivo remain incompletely understood. Studies of mice with homozygous disruption of the Pctp gene have largely refuted the hypotheses that this protein participates in the hepatocellular selection and transport of biliary phospholipids, in the production of lung surfactant, in leukotriene biosynthesis and in cellular phosphatidylcholine metabolism. Nevertheless, Pctp −/− mice exhibit interesting defects in lipid homeostasis, the understanding of which should elucidate the biological functions of PC-TP.
Phosphatidylcholine transfer protein (PC-TP, synonym StARD2) is a highly specific intracellular lipid binding protein that is enriched in liver. Coding region polymorphisms in both humans and mice appear to confer protection against measures of insulin resistance. The current study was designed to test the hypotheses that Pctp−/− mice are protected against diet-induced increases in hepatic glucose production and that small molecule inhibition of PC-TP recapitulates this phenotype. Pctp−/− and wild type mice were subjected to high fat feeding, and rates of hepatic glucose production and glucose clearance were quantified by hyperinsulinemic euglycemic clamp studies and pyruvate tolerance tests. These studies revealed that high fat diet-induced increases in hepatic glucose production were markedly attenuated in Pctp−/− mice. Small molecule inhibitors of PC-TP were synthesized and their potencies, as well as mechanism of inhibition, were characterized in vitro. An optimized inhibitor was administered to high fat fed mice and used to explore effects on insulin signaling in cell culture systems. Small molecule inhibitors bound PC-TP, displaced phosphatidylcholines from the lipid binding site and increased the thermal stability of the protein. Administration of the optimized inhibitor to wild type mice attenuated hepatic glucose production associated with high fat feeding, but had no activity in Pctp−/− mice. Indicative of a mechanism for reducing glucose intolerance that is distinct from commonly utilized insulin-sensitizing agents, the inhibitor promoted insulin-independent phosphorylation of key insulin signaling molecules. These findings suggest PC-TP inhibition as a novel therapeutic strategy in the management of hepatic insulin resistance.
Grapefruit juice (GJ), a cytochrome P450 (CYP) 3A4 inhibitor, may affect the pharmacokinetics of drugs metabolized through CYP 3A4. Losartan, an angiotensin II antagonist, is converted into its main active metabolite E3174 by CYP 3A4 and CYP 2C9. The effect of GJ on losartan pharmacokinetics was assessed in a randomized crossover trial. Losartan was given to 9 volunteers with and without GJ. Concentrations of losartan and its E3174 metabolite were determined in serum by a high-performance liquid chromatography method (HPLC). Significant differences were observed in some of the pharmacokinetic parameters of losartan and its metabolite E3174 after losartan administration with and without co-administered GJ. The lag time (time to drug appearance in serum) of losartan increased significantly with co-administered GJ. The mean residence time (MRT) and half-life (t(1/2)) of the E3174 metabolite were significantly longer and the area under the concentration--time curve (AUC) of the E3174 metabolite was significantly smaller after concomitant GJ administration. The ratio AUC(losartan)/AUC(E3174) was significantly increased after concurrent grapefruit juice intake. The increased lag time of losartan and the increased MRT and t1/2 and decreased AUC of E3174 were considered indicative of simultaneous CYP 3A4 inhibition and P-glycoprotein activation. The significantly increased AUC(losartan)/AUC(E3174) ratio, however, indicates reduced losartan conversion to E3174 by CYP 3A4 metabolism as a result of co-administered GJ.
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