Role of insulin signaling in the development of metabolic dysfunction-associated fatty liver disease

概要

［課程－２］
審査の結果の要旨
氏名

チッタフーン ワノルラト

The present study aims to explore the potential mechanistic relationship of
hyperinsulinemia, insulin resistance, and the elevation of PPARγ underlying the
development of hepatic steatosis, which is the essential component of metabolic
dysfunction-associated fatty liver disease (MAFLD). The high-fat diet (HFD)-fed, db/db,
and liver-specific insulin receptor substrate 1 and 2 knockout (LIRS1/2DKO) mice were
prepared and analyzed. The following results were obtained.
1. In parallel to the development of hepatic steatosis, both HFD-fed and db/db mice
exhibited excessive accumulation of hepatic cAMP. This was due to the insulininduced repression of the cAMP transporter, multidrug resistance-associated
protein 4 (MRP4).
2. The overaccumulation of cAMP levels led to the augmentation of PPARγ mRNA
levels in the liver, which was mediated by the endoplasmic reticulum (ER) stressinduced FoxO6 upregulation. Consequently, the triglyceride (TG) accumulation
in the liver was increased. In contrast, the inhibition of ER stress or the ablation
of FoxO6 substantially mitigated cAMP-induced PPARγ upregulation, leading to
the lowered hepatic TG concentration.
3. On the other hand, in mice-lacking hepatic insulin signaling (LIRS1/2DKO mice),
which did not develop hepatic steatosis, the Mrp4-mediated cAMP extrusion
remined intact. Additionally, the ER stress response was remarkably low in
LIRS1/2DKO mice, coupled with decreased FoxO6 and PPARγ expression levels.
Taken together, these results manifest that the overabundance of hepatic cAMP,
caused by the reduction of MRP4, plays an indispensable role in the pathogenesis of
hepatic steatosis under the hyperinsulinemic and insulin-resistant condition, whereby
the steatohepatic mice displayed the unrestraint ER stress response, accompanied with
increased expression levels of FoxO6 and PPARγ. Therefore, approaches that enhance
the MRP4-mediated cAMP egress in the liver could possibly serve as a novel therapeutic
strategy for the treatment of hepatic steatosis, which would also provide the therapeutic
benefits to MAFLD.
よって本論文は博士（医学 ）の学位請求論文として合格と認められる。