| Authors |
Ye R, Gordillo R, Shao M, Onodera T, Chen Z, Chen S, Lin X, SoRelle JA, Li X,
Tang M, Keller MP, Kuliawat R, Attie AD, Gupta RK, Holland WL, Beutler B, Herz
J, Scherer PE
|
| Submitted By |
Alan Attie on 11/5/2018 |
| Status |
Published |
| Journal |
The Journal of clinical investigation |
| Year |
2018 |
| Date Published |
3/1/2018 |
| Volume : Pages |
128 : 1178 - 1189 |
| PubMed Reference |
|
| Abstract |
The compensatory proliferation of insulin-producing 脽 cells is critical to
maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure
of 脽 cells to proliferate results in hyperglycemia and insulin dependence in
patients. To understand the effect of the interplay between 脽 cell compensation
and lipid metabolism upon obesity and peripheral insulin resistance, we
eliminated LDL receptor-related protein 1 (LRP1), a pleiotropic mediator of
cholesterol, insulin, energy metabolism, and other cellular processes, in 脽
cells. Upon high-fat diet exposure, LRP1 ablation significantly impaired insulin
secretion and proliferation of 脽 cells. The diminished insulin signaling was
partly contributed to by the hypersensitivity to glucose-induced, Ca2+-dependent
activation of Erk and the mTORC1 effector p85 S6K1. Surprisingly, in
LRP1-deficient islets, lipotoxic sphingolipids were mitigated by improved lipid
metabolism, mediated at least in part by the master transcriptional regulator
PPAR?2. Acute overexpression of PPAR?2 in 脽 cells impaired insulin signaling and
insulin secretion. Elimination of Apbb2, a functional regulator of LRP1
cytoplasmic domain, also impaired 脽 cell function in a similar fashion. In
summary, our results uncover the double-edged effects of intracellular lipid
metabolism on 脽 cell function and viability in obesity and type 2 diabetes and
highlight LRP1 as an essential regulator of these processes.
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