Fenofibrate simultaneously induces hepatic fatty acid oxidation, synthesis, and elongation in mice - PubMed (original) (raw)

Fenofibrate simultaneously induces hepatic fatty acid oxidation, synthesis, and elongation in mice

Maaike H Oosterveer et al. J Biol Chem. 2009.

Abstract

A growing body of evidence indicates that peroxisome proliferator-activated receptor alpha (PPARalpha) not merely serves as a transcriptional regulator of fatty acid catabolism but also exerts a much broader role in hepatic lipid metabolism. We determined adaptations in hepatic lipid metabolism and related aspects of carbohydrate metabolism upon treatment of C57Bl/6 mice with the PPARalpha agonist fenofibrate. Stable isotope procedures were applied to assess hepatic fatty acid synthesis, fatty acid elongation, and carbohydrate metabolism. Fenofibrate treatment strongly induced hepatic de novo lipogenesis and chain elongation (+/-300, 150, and 600% for C16:0, C18:0, and C18:1 synthesis, respectively) in parallel with an increased expression of lipogenic genes. The lipogenic induction in fenofibrate-treated mice was found to depend on sterol regulatory element-binding protein 1c (SREBP-1c) but not carbohydrate response element-binding protein (ChREBP). Fenofibrate treatment resulted in a reduced contribution of glycolysis to acetyl-CoA production, whereas the cycling of glucose 6-phosphate through the pentose phosphate pathway presumably was enhanced. Altogether, our data indicate that beta-oxidation and lipogenesis are induced simultaneously upon fenofibrate treatment. These observations may reflect a physiological mechanism by which PPARalpha and SREBP-1c collectively ensure proper handling of fatty acids to protect the liver against cytotoxic damage.

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Figures

FIGURE 1.

Hepatic fatty acid synthesis in control and fenofibrate-treated mice. Conscious, unrestrained C57Bl/6 mice were infused with sodium [1-13C]acetate. Fatty acids from total liver homogenates and TG fractions were derivatized, and isotopomer patterns were determined by GC-MS analysis. Synthesis rates and contribution of de novo lipogenesis and chain elongation were calculated using MIDA. A, fractional synthesis rates of total and TG-derived palmitate from de novo lipogenesis. B, fractional synthesis rates of total and TG-derived stearate from elongation of labeled (de novo synthesized; C16:0 DNL) and unlabeled (pre-existing; C16:0 PE) palmitate. C, fractional synthesis rates of total and TG-derived oleate from elongation of labeled and unlabeled palmitate. D, acetyl-CoA precursor pool enrichments in total and TG-derived palmitate. Open bars, control group; filled bars, fenofibrate-treated group. Values represent means ± S.E. for n = 6–8; *, p < 0.05 fenofibrate versus control (Mann-Whitney U test).

FIGURE 2.

Transcriptional control of lipogenic gene expression in control and fenofibrate-treated mice. _Srebp-1c_−/− and _Chrebp_−/− mice and their wild-type littermates were sacrificed by cardiac puncture. Gene expression levels in livers were determined by quantitative PCR and normalized for 18S expression. Expression levels of untreated mice of each genotype were set to 1. A, expression of genes involved in fatty acid synthesis in _Srebp-1c_−/− mice and wild-type littermates. B, expression of genes involved in fatty acid synthesis in _Chrebp_−/− mice and wild-type littermates. Open bars, wild-type control group; filled bars, wild-type fenofibrate-treated group; dashed bars, knock-out control group; dotted bars, knock-out fenofibrate-treated group. Values represent means ± S.E. for n = 4; *, p < 0.05 fenofibrate versus control (Mann-Whitney U test).

FIGURE 3.

Hepatic glucose metabolism in control and fenofibrate-treated mice. Conscious, unrestrained C57Bl/6 mice were infused with different stable isotopes, and carbohydrate fluxes were calculated from GC-MS analysis of blood and urine spots obtained at regular time intervals under steady-state conditions (t = 180–360 min) using MIDA. A, glucokinase flux. B, gluconeogenic (GNG) flux and partitioning toward glucose (light gray bars) and UDP-glucose (dark gray bars). C, hepatic glucose production rate and contribution of gluconeogenic flux or rate of appearance of endogenous glucose (Ra) (glc; endo) (light gray bars) and glucose cycling (dark gray bars). D, glycogen phosphorylase flux. E and F, glycogen balance (E) and abundance (F) of triple labeled molecules in blood and UDP-glucose. Open bars, control group; filled bars, fenofibrate-treated group. Values represent means ± S.E. for n = 5–6; *, p < 0.05 fenofibrate versus control (analysis of variance for repeated measurements).

FIGURE 4.

Hepatic Glc-6-P and glycogen content in control and fenofibrate-treated mice. C57Bl/6 mice were sacrificed by cardiac puncture. Hepatic Glc-6-P and glycogen content were determined using enzymatic assays. Open bars, control group; filled bars, fenofibrate-treated group. Values represent means ± S.E. for n = 6; *, p < 0.05 fenofibrate versus control (Mann-Whitney U test).

FIGURE 5.

Remodeling of hepatic intermediary metabolism in fenofibrate-treated mice. Fenofibrate treatment promotes adipose tissue lipolysis, thereby enhancing hepatic influx of glycerol and fatty acids. In the liver, fenofibrate promotes fatty acid β-oxidation in peroxisomes and mitochondria. PPARα target genes are indicated in blue (see also Ref. 5). Acetyl-CoA generated by β-oxidation is used for ketogenesis and energy supply but also serves as a substrate for fatty acid synthesis via de novo lipogenesis and fatty acid elongation. Acetyl-CoA transport over the mitochondrial membrane is facilitated by increased pyruvate/malate cycling, which generates NADPH to support the lipogenic flux. In parallel, hepatic glucose uptake and glycolysis are suppressed, and the contribution of acetyl-CoA from hepatic glucose metabolism to the lipogenic flux is consequently reduced. Glycerol is converted into glucose 6-phosphate via the gluconeogenic pathway. Glucose 6-phosphate (G-6-P) cycles through the pentose phosphate pathway to triose phosphate and back to Glc-6-P and PPP, thereby generating NADPH.

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Fenofibrate simultaneously induces hepatic fatty acid oxidation, synthesis, and elongation in mice - PubMed (original) (raw)