Cardiovasc Prev Pharmacother.  2022 Apr;4(2):57-62. 10.36011/cpp.2022.4.e9.

Targets for rescue from fatty acid-induced lipotoxicity in pancreatic beta cells

• Hong SW
• Lee WY

• KMID: 2536921
• DOI: http://doi.org/10.36011/cpp.2022.4.e9

Abstract

A persistent intake of excess calories increases plasma levels of free fatty acids, particularly the saturated form that has been shown to exert toxic effects on pancreatic beta cells by inducing dysfunction and apoptosis (i.e., lipotoxicity). An insufficient supply of insulin due to beta cell failure is a major factor in the onset and progression of type 2 diabetes; therefore, it is crucial to understand the cellular mechanisms of lipotoxicity to prevent beta cell failure. Many studies on the effects of lipotoxicity have demonstrated the various factors responsible for beta cell impairment, but the mechanisms of dysfunction and apoptosis resulting from lipotoxicity have not been fully described. This review discusses lipotoxicity-induced alterations of cellular mechanisms, and assesses drugs such as incretin mimetics, thiazolidinedione, and clusterin. Understanding the molecular mechanisms of lipotoxicity-induced beta cell failure is useful in guiding the development of new therapeutic targets for diabetes treatment.

Keyword

Pancreatic beta cell; Lipotoxicity; Inflammation; Endoplasmic recticulum stress; Autophagy

Figure

• 

  Fig. 1. Summary of lipotoxicity by fatty acids (FAs) and autophagy activation by clusterin. (A) Chronic exposure to FAs induces beta cell dysfunction and apoptosis through cellular lipid synthesis, inflammation, and endoplasmic reticulum (ER) stress. Activated sterol regulatory element-binding protein-1c (SREBP1c) by FAs is translocated to the nucleus and upregulates the expression of fatty acid synthase (Fas) and acetyl-CoA carboxylase-1 (Acc1) for synthesis of cellular lipid. Expression of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1β, is upregulated by c-Jun N-terminal kinase (JNK)/nuclear factor-kappa B (NF-κB) activation, and severe ER stress by FAs ultimately causes the expression of C/EBP homologous protein (CHOP), an apoptotic protein. This alteration of cellular mechanisms is a strong inducer of the apoptosis of pancreatic beta cells. Exendin-4 (Ex-4) or pioglitazone (PIO) showed a strong effect in the rescue of pancreatic beta cells from lipotoxicity. Treatment with Ex-4 maintains lipid metabolism by repressing the activation of SREBP1c. Pioglitazone blocks inflammatory responses repressing JNK/NF-κB activation and decreases CHOP expression mediated by the attenuation of ER stress. Protein kinase RNA-like endoplasmic reticulum kinase (PERK), Activating transcription factor-4 (ATF4), phosphorylated eukaryotic translation initiation factor 2 alpha subunit (pe-IF2α). (B) Autophagy activation protects pancreatic beta cells from lipotoxicity. Clusterin (CLU) facilitates the binding of microtubule-associated protein light chain 3 (LC3) with autophagy-related gene-3 (Atg3) and p62, activating autophagy.

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