bims-sikglu 2024-08-25 papers

Issue of 2024‒08‒25
three papers selected by
Dipsikha Biswas, Københavns Universitet and Maria Madrazo i Montoya, Københavns Universitet

Biomed Pharmacother. 2024 Aug 16. pii: S0753-3322(24)01187-9. [Epub ahead of print]179 117303

PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells.

Meijian Zhang, Emma Barroso, Lucía Peña, Patricia Rada, Ángela M Valverde, Walter Wahli, Xavier Palomer, Manuel Vázquez-Carrera.

The role of peroxisome proliferator-activated receptor (PPAR)β/δ in hepatic fibrosis remains a subject of debate. Here, we examined the effects of a PPARβ/δ agonist on the pathogenesis of liver fibrosis and the activation of hepatic stellate cells (HSCs), the main effector cells in liver fibrosis, in response to the pro-fibrotic stimulus transforming growth factor-β (TGF-β). The PPARβ/δ agonist GW501516 completely prevented glucose intolerance and peripheral insulin resistance, blocked the accumulation of collagen in the liver, and attenuated the expression of inflammatory and fibrogenic genes in mice fed a choline-deficient high-fat diet (CD-HFD). The antifibrogenic effect of GW501516 observed in the livers CD-HFD-fed mice could occur through an action on HSCs since primary HSCs isolated from Ppard-/- mice showed increased mRNA levels of the profibrotic gene Col1a1. Moreover, PPARβ/δ activation abrogated TGF-β1-mediated cell migration (an indicator of cell activation) in LX-2 cells (immortalized activated human HSCs). Likewise, GW501516 attenuated the phosphorylation of the main downstream intracellular protein target of TGF-β1, suppressor of mothers against decapentaplegic (SMAD)3, as well as the levels of the SMAD3 co-activator p300 via the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) in LX-2 cells. Overall, these findings uncover a new mechanism by which the activation of AMPK by a PPARβ/δ agonist reduces TGF-β1-mediated activation of HSCs and fibrosis via the reduction of both SMAD3 phosphorylation and p300 levels.

Keywords: AMPK; ERK1/2; Fibrosis; LX-2; P300; PPARβ/δ

DOI: https://doi.org/10.1016/j.biopha.2024.117303

Essays Biochem. 2024 Aug 23. pii: EBC20240008. [Epub ahead of print]

New concepts in the roles of AMPK in adipocyte stem cell biology.

Alice E Pollard.

Obesity is a major risk factor for many life-threatening diseases. Adipose tissue dysfunction is emerging as a driving factor in the transition from excess adiposity to comorbidities such as metabolic-associated fatty liver disease, cardiovascular disease, Type 2 diabetes and cancer. However, the transition from healthy adipose expansion to the development of these conditions is poorly understood. Adipose stem cells, residing in the vasculature and stromal regions of subcutaneous and visceral depots, are responsible for the expansion and maintenance of organ function, and are now recognised as key mediators of pathological transformation. Impaired tissue expansion drives inflammation, dysregulation of endocrine function and the deposition of lipids in the liver, muscle and around vital organs, where it is toxic. Contrary to previous hypotheses, it is the promotion of healthy adipose tissue expansion and function, not inhibition of adipogenesis, that presents the most attractive therapeutic strategy in the treatment of metabolic disease. AMP-activated protein kinase, a master regulator of energy homeostasis, has been regarded as one such target, due to its central role in adipose tissue lipid metabolism, and its apparent inhibition of adipogenesis. However, recent studies utilising AMP-activated protein kinase (AMPK)-specific compounds highlight a more subtle, time-dependent role for AMPK in the process of adipogenesis, and in a previously unexplored repression of leptin, independent of adipocyte maturity. In this article, I discuss historic evidence for AMPK-mediated adipogenesis inhibition and the multi-faceted roles for AMPK in adipose tissue.

Keywords: AMPK; Adipose; leptins; lipid metabolism

DOI: https://doi.org/10.1042/EBC20240008

Endocrinology. 2024 Aug 19. pii: bqae107. [Epub ahead of print]

SIK2 and SIK3 differentially regulate mouse granulosa cell response to exogenous gonadotropins in vivo.

Emily T Hayes, Mariam Hassan, Oliwia Lakomy, Rachael Filzen, Marah Armouti, Marc Foretz, Noriyuki Tsumaki, Hiroshi Takemori, Carlos Stocco.

Salt-inducible kinases (SIKs), a family of serine/threonine kinases, were found to be critical determinants of female fertility. SIK2 silencing results in increased ovulatory response to gonadotropins. In contrast, SIK3 knockout results in infertility, gonadotropin insensitivity, and ovaries devoid of antral and preovulatory follicles. This study hypothesizes that SIK2 and SIK3 differentially regulate follicle growth and fertility via contrasting actions in the granulosa cells (GCs), the somatic cells of the follicle. Therefore, SIK2 or SIK3 GC-specific knockdown (SIK2GCKD and SIK3GCKD, respectively) mice were generated by crossing SIK floxed mice with Cyp19a1pII-Cre mice. Fertility studies revealed that pup accumulation over six months and the average litter size of SIK2GCKD mice are similar to controls, though SIK3GCKD mice are significantly lower compared to controls. Compared to controls, gonadotropin stimulation of prepubertal SIK2GCKD mice results in significantly higher serum estradiol levels, whereas SIK3GCKD mice produced significantly less estradiol. Cyp11a1, Cyp19a1, and StAR were significantly increased in the GCs of gonadotropin-stimulated SIK2GCKD mice. However, Cyp11a1 and StAR remained significantly lower than controls in SIK3GCKD mice. Interestingly, Cyp19a1 stimulation in SIK3GCKD was not statistically different compared to controls. Superovulation resulted in SIK2GCKD mice ovulating significantly more oocytes, whereas SIK3GCKD mice ovulated significantly fewer oocytes than controls. Remarkably, SIK3GCKD superovulated ovaries contained significantly more preantral follicles than controls. SIK3GCKD ovaries contained significantly more apoptotic cells and fewer proliferating cells than controls. This data points to the differential regulation of GC function and follicle development by SIK2 and SIK3 and supports the therapeutic potential of targeting these kinases for treating infertility or developing new contraceptives.

Keywords: SIK2; SIK3; female fertility; granulosa cells; ovary

DOI: https://doi.org/10.1210/endocr/bqae107