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. 2013 Jun;62(6):2095-105.
doi: 10.2337/db12-1397. Epub 2013 Jan 24.

Activation of PPARα ameliorates hepatic insulin resistance and steatosis in high fructose-fed mice despite increased endoplasmic reticulum stress

Stanley M H Chan  1 , Ruo-Qiong Sun, Xiao-Yi Zeng, Zi-Heng Choong, Hao Wang, Matthew J Watt, Ji-Ming Ye
Affiliations

Activation of PPARα ameliorates hepatic insulin resistance and steatosis in high fructose-fed mice despite increased endoplasmic reticulum stress

Stanley M H Chan et al. Diabetes. 2013 Jun.

Abstract

Endoplasmic reticulum (ER) stress is suggested to cause hepatic insulin resistance by increasing de novo lipogenesis (DNL) and directly interfering with insulin signaling through the activation of the c-Jun N-terminal kinase (JNK) and IκB kinase (IKK) pathway. The current study interrogated these two proposed mechanisms in a mouse model of hepatic insulin resistance induced by a high fructose (HFru) diet with the treatment of fenofibrate (FB) 100 mg/kg/day, a peroxisome proliferator-activated receptor α (PPARα) agonist known to reduce lipid accumulation while maintaining elevated DNL in the liver. FB administration completely corrected HFru-induced glucose intolerance, hepatic steatosis, and the impaired hepatic insulin signaling (pAkt and pGSK3β). Of note, both the IRE1/XBP1 and PERK/eIF2α arms of unfolded protein response (UPR) signaling were activated. While retaining the elevated DNL (indicated by the upregulation of SREBP1c, ACC, FAS, and SCD1 and [3H]H2O incorporation into lipids), FB treatment markedly increased fatty acid oxidation (indicated by induction of ACOX1, p-ACC, β-HAD activity, and [14C]palmitate oxidation) and eliminated the accumulation of diacylglycerols (DAGs), which is known to have an impact on insulin signaling. Despite the marked activation of UPR signaling, neither JNK nor IKK appeared to be activated. These findings suggest that lipid accumulation (mainly DAGs), rather than the activation of JNK or IKK, is pivotal for ER stress to cause hepatic insulin resistance. Therefore, by reducing the accumulation of deleterious lipids, activation of PPARα can ameliorate hepatic insulin resistance against increased ER stress.

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Figures

FIG. 1.
FIG. 1.
Effects of FB treatment on glucose tolerance. Male C57BL/6J mice were fed an HFru diet with or without the supplementation of FB 100 mg/kg/day compared with a standard laboratory CH diet. The experiments were performed after 2 weeks of CH, CH-FB, HFru, or HFru-FB feeding. A: GTT was performed with an injection of glucose 2.5 g/kg i.p. after 5–7 h of fasting. B: Incremental area under the curve (iAUC) for blood glucose level. C: Plasma insulin level between 30–60 min of GTT. Data are mean ± SE, 8–12 mice per group. *P < 0.05; ††P < 0.01 of the compared groups.
FIG. 2.
FIG. 2.
Effects of FB treatment on hepatic insulin signal transduction. After 2 weeks of feeding, animals were fasted for 5–7 h before tissue collection, and liver homogenates were prepared for immunoblotting. A: Representative blots of phosphorylated (p) and total (t) Akt (Ser473) with densitometry in the liver. B: Representative blots of p- and t-GSK3β (Ser21/9) with densitometry in the liver in response to a bolus of insulin stimulation of 2 U/kg i.p. Each lane represents a single mouse. Data are mean ± SE, 8 mice per group. All insulin-stimulated groups reached statistical significance of P < 0.01 compared with their corresponding basal groups, unless otherwise indicated. **P < 0.01; ††P < 0.001 of the compared groups.
FIG. 3.
FIG. 3.
Effects of FB treatment on hepatic lipid content. After 2 weeks of feeding, animals were fasted for 5–7 h before tissue collection, and liver homogenates were extracted for the assessment of total TG (A), DAG (B), and ceramide (C) content. Data are mean ± SE, 8 mice per group. **P < 0.01; †P < 0.05; ††P < 0.001 of the compared groups.
FIG. 4.
FIG. 4.
Effects of FB treatment on key enzymes of FA oxidation. After 2 weeks of feeding, animals were fasted for 5–7 h before tissue collection, and liver homogenates were immunoblotted for key enzymes related to oxidative capacity. Representative blots of ACOX1 (A), phosphorylated (p) ACC (Ser79) (B), the specific activities of β-HAD (C), and citrate synthase (D). Each lane represents a single mouse. Data are mean ± SE, 10 mice per group. E: Hepatic FA oxidation was measured in separate liver homogenates with [14C]palmitate as a substrate in the presence or absence of 0.02 mmol/L etomoxir. Data are mean ± SE, 6–8 mice per group. *P < 0.05; **P < 0.01 vs. CH; †P < 0.05; ††P < 0.001 of the compared groups.
FIG. 5.
FIG. 5.
Effects of FB treatment on hepatic UPR signaling. After 2 weeks of feeding, animals were fasted for 5–7 h before tissue collection, and liver homogenates were immunoblotted for markers of ER stress. Representative blots of phosphorylated (p) IRE1 (Ser724) (A), sXBP1 (B), p-PERK (Thr980) (C), p-eIF2α (Ser51) (D), CHOP (E), and GADD34 (F) with densitometry. Each lane represents a single mouse. Data are mean ± SE, 8–10 mice per group. *P < 0.01, P < 0.01 vs. CH; ††P < 0.01 of the compared groups.
FIG. 6.
FIG. 6.
Effects of FB treatment on hepatic DNL. After 2 weeks of feeding, animals were fasted for 5–7 h before tissue collection, and liver homogenates were immunoblotted for key enzymes related to lipogenic capacity. Representative blots of the mSREBP1c (A), total (t) ACC (B), FAS (C), and SCD1 (D) with densitometry. Data are mean ± SE, 10 mice per group. E: Hepatic DNL was measured by the incorporation of [3H]H2O into hepatic TG. Data are mean ± SE, 6–8 mice per group. *P < 0.05; **P < 0.01 vs. CH; ††P < 0.001 of the compared groups.
FIG. 7.
FIG. 7.
Effects of FB treatment on JNK and IKK activation. After 2 weeks of feeding, animals were fasted for 5–7 h before tissue collection, and liver homogenates were immunoblotted for evidence of JNK and IKK activation. Representative blots of phosphorylated (p) JNK (Thr183/Tyr185) (A), p-IKKα/β (Ser176/Ser177) (B), and IκBα (C). Data are mean ± SE, 8 mice per group.
FIG. 8.
FIG. 8.
Illustration of PPARα-mediated effects on ER stress, lipid metabolism, and insulin sensitivity in the liver. HFru feeding accentuates the accumulation of TG and DAG in the liver through the induction of DNL. The accumulation of these lipid metabolites attenuates normal insulin signal transduction leading to hepatic insulin resistance, resulting in the reduction of glucose tolerance. PPARα activation by FB may also directly stimulate lipogenesis, which may involve the signaling of specific arms of the UPR pathways. However, the predominant effect of potentiated oxidative capacity (primarily peroxisomal oxidation) driven by PPARα is capable of eliminating lipid accumulation, thus overcoming fructose-induced hepatic insulin resistance (IR) and glucose intolerance.
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