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Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects million women worldwide, presenting a complex pathophysiology that has not been fully elucidated yet. Recently, it has been suggested that PCOS triggers the endoplasmic reticulum (ER) stress, thus being associated with unfolded protein response (UPR) activation. Indeed, the UPR response has been associated with several pathological conditions, including in the reproductive system. Several studies demonstrated that ovarian UPR markers are upregulated in PCOS, being associated with worst ovarian outcomes, and this was ameliorated by ER stress inhibition. In this review, we aim to summarize the main findings from previous studies covering this topic, in an attempt to clarify the potential role of ER stress and the UPR response in the pathophysiology of PCOS. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress poses a new pathological mechanism for metabolic-associated fatty liver disease (MAFLD). MAFLD treatment has encompassed renin-angiotensin system (RAS) blockers and aerobic exercise training, but their association with hepatic ER stress is not well known. Therefore, we aimed to compare the effects of hepatic RAS modulation by enalapril and/or aerobic exercise training over ER stress in MAFLD caused by a diet-induced obesity model. C57BL/6 mice were fed a standard-chow (CON, n = 10) or a high-fat (HF, n = 40) diet for 8 weeks. HF group was then randomly divided into: HF (n = 10), HF + Enalapril (EN, n = 10), HF + Aerobic exercise training (AET, n = 10), and HF + Enalapril+Aerobic exercise training (EN + AET, n = 10) for 8 more weeks. Body mass (BM) and glucose profile were evaluated. In the liver, ACE and ACE2 activity, morphology, lipid profile, and protein expression of ER stress and metabolic markers were assessed. Both enalapril and aerobic exercise training provided comparable efficacy in improving diet-induced MAFLD through modulation of RAS and ER stress, but the latter was more efficient in improving ER stress, liver damage and metabolism. This is the first study to evaluate pharmacological (enalapril) and non-pharmacological (aerobic exercise training) RAS modulators associated with ER stress in a diet-induced MAFLD model. HF diet led to favoring of the RAS classical arm and increased ER stress through higher expression of the eIF2α pathway. These results could be related to HF diet-associated insulin resistance and upregulation of gluconeogenesis enzymes PEPCK and G6Pase, as well as lipid accumulation through increased lipogenic transcription factor SREBP1c and lower PPARα levels. Enalapril treatment, aerobic exercise training, and the combination of both interventions were able to favor the RAS counterregulatory arm, improve ER stress and decrease lipid accumulation. All interventions were also able to improve insulin resistance, although aerobic exercise training showed more efficiency, reverting glucose intolerance and decreasing the expression of PEPCK. Aerobic exercise training was also the only intervention able to reduce binucleation of hepatocytes and the association with enalapril treatment reverted the increase in hepatocytes with two or more nuclei, which could be suggestive of liver damage associated with the pharmacological treatment. [Display omitted] • Enalapril and aerobic exercise training decrease ACE/ACE2 ratio in obese mice. • RAS counterregulatory arm could be associated to decreased ER stress markers in MAFLD. • Aerobic exercise training better improved liver ER stress markers, metabolism and damage. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress poses a new pathological mechanism for metabolic-associated fatty liver disease (MAFLD). MAFLD treatment has encompassed renin-angiotensin system (RAS) blockers and aerobic exercise training, but their association with hepatic ER stress is not well known. Therefore, we aimed to compare the effects of hepatic RAS modulation by enalapril and/or aerobic exercise training over ER stress in MAFLD caused by a diet-induced obesity model. C57BL/6 mice were fed a standard-chow (CON, n = 10) or a high-fat (HF, n = 40) diet for 8 weeks. HF group was then randomly divided into: HF (n = 10), HF + Enalapril (EN, n = 10), HF + Aerobic exercise training (AET, n = 10), and HF + Enalapril+Aerobic exercise training (EN + AET, n = 10) for 8 more weeks. Body mass (BM) and glucose profile were evaluated. In the liver, ACE and ACE2 activity, morphology, lipid profile, and protein expression of ER stress and metabolic markers were assessed. Both enalapril and aerobic exercise training provided comparable efficacy in improving diet-induced MAFLD through modulation of RAS and ER stress, but the latter was more efficient in improving ER stress, liver damage and metabolism. This is the first study to evaluate pharmacological (enalapril) and non-pharmacological (aerobic exercise training) RAS modulators associated with ER stress in a diet-induced MAFLD model. HF diet led to favoring of the RAS classical arm and increased ER stress through higher expression of the eIF2α pathway. These results could be related to HF diet-associated insulin resistance and upregulation of gluconeogenesis enzymes PEPCK and G6Pase, as well as lipid accumulation through increased lipogenic transcription factor SREBP1c and lower PPARα levels. Enalapril treatment, aerobic exercise training, and the combination of both interventions were able to favor the RAS counterregulatory arm, improve ER stress and decrease lipid accumulation. All interventions were also able to improve insulin resistance, although aerobic exercise training showed more efficiency, reverting glucose intolerance and decreasing the expression of PEPCK. Aerobic exercise training was also the only intervention able to reduce binucleation of hepatocytes and the association with enalapril treatment reverted the increase in hepatocytes with two or more nuclei, which could be suggestive of liver damage associated with the pharmacological treatment. [Display omitted] • Enalapril and aerobic exercise training decrease ACE/ACE2 ratio in obese mice. • RAS counterregulatory arm could be associated to decreased ER stress markers in MAFLD. • Aerobic exercise training better improved liver ER stress markers, metabolism and damage. [ABSTRACT FROM AUTHOR]

Perturbations of intracellular magnesium (Mg2+) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg2+ across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH). Serum Mg2+ levels and hepatic CNNM4 expression were characterised in clinical samples. Primary hepatocytes were cultured under methionine and choline deprivation. A 0.1% methionine and choline-deficient diet, or a choline-deficient high-fat diet were used to induce NASH in our in vivo rodent models. Cnnm4 was silenced using siRNA, in vitro with DharmaFECT and in vivo with Invivofectamine® or conjugated to N-acetylgalactosamine. Patients with NASH showed hepatic CNNM4 overexpression and dysregulated Mg2+ levels in the serum. Cnnm4 silencing ameliorated hepatic lipid accumulation, inflammation and fibrosis in the rodent NASH models. Mechanistically, CNNM4 knockdown in hepatocytes induced cellular Mg2+ accumulation, reduced endoplasmic reticulum stress, and increased microsomal triglyceride transfer activity, which promoted hepatic lipid clearance by increasing the secretion of VLDLs. CNNM4 is overexpressed in patients with NASH and is responsible for dysregulated Mg2+ transport. Hepatic CNNM4 is a promising therapeutic target for the treatment of NASH. Cyclin M4 (CNNM4) is overexpressed in non-alcoholic steatohepatitis (NASH) and promotes the export of magnesium from the liver. The liver-specific silencing of Cnnm4 ameliorates NASH by reducing endoplasmic reticulum stress and promoting the activity of microsomal triglyceride transfer protein. [Display omitted] • CNNM4 acts as a magnesium exporter in the liver. Its upregulation in NASH leads to elevated magnesium levels in serum. • Liver-specific CNNM4 targeting alleviates steatosis, inflammation, and fibrosis in preclinical NASH models. • siRNA-mediated CNNM4 downregulation promotes hepatic magnesium accumulation and reduces endoplasmic reticulum stress. • Silencing CNNM4 enhances microsomal triglyceride transfer protein activity leading to VLDL assembly and secretion. [ABSTRACT FROM AUTHOR]