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.