Autophagy is a conserved quality-control pathway that degrades cytoplasmic contents in lysosomes. Autophagy degrades lipid droplets through a process termed lipophagy. Starvation and an acute lipid ...stimulus increase autophagic sequestration of lipid droplets and their degradation in lysosomes. Accordingly, liver-specific deletion of the autophagy gene
Atg7
increases hepatic fat content, mimicking the human condition termed nonalcoholic fatty liver disease. In this review, we provide insights into the molecular regulation of lipophagy, discuss fundamental questions related to the mechanisms by which autophagosomes recognize lipid droplets and how ATG proteins regulate membrane curvature for lipid droplet sequestration, and comment on the possibility of cross talk between lipophagy and cytosolic lipases in lipid mobilization. Finally, we discuss the contribution of lipophagy to the pathophysiology of human fatty liver disease. Understanding how lipophagy clears hepatocellular lipid droplets could provide new ways to prevent fatty liver disease, a major epidemic in developed nations.
Background & Aims Hepatic de-differentiation, liver development, and malignant transformation are processes in which the levels of hepatic S-adenosylmethionine are tightly regulated by 2 genes: ...methionine adenosyltransferase 1A ( MAT1A ) and methionine adenosyltransferase 2A ( MAT2A ). MAT1A is expressed in the adult liver, whereas MAT2A expression primarily is extrahepatic and is associated strongly with liver proliferation. The mechanisms that regulate these expression patterns are not completely understood. Methods In silico analysis of the 3′ untranslated region of MAT1A and MAT2A revealed putative binding sites for the RNA-binding proteins AU-rich RNA binding factor 1 (AUF1) and HuR, respectively. We investigated the posttranscriptional regulation of MAT1A and MAT2A by AUF1, HuR, and methyl-HuR in the aforementioned biological processes. Results During hepatic de-differentiation, the switch between MAT1A and MAT2A coincided with an increase in HuR and AUF1 expression. S-adenosylmethionine treatment altered this homeostasis by shifting the balance of AUF1 and methyl-HuR/HuR, which was identified as an inhibitor of MAT2A messenger RNA (mRNA) stability. We also observed a similar temporal distribution and a functional link between HuR, methyl-HuR, AUF1, and MAT1A and MAT2A during fetal liver development. Immunofluorescent analysis revealed increased levels of HuR and AUF1, and a decrease in methyl-HuR levels in human livers with hepatocellular carcinoma (HCC). Conclusions Our data strongly support a role for AUF1 and HuR/methyl-HuR in liver de-differentiation, development, and human HCC progression through the posttranslational regulation of MAT1A and MAT2A mRNAs.
To develop a predictive model for successful cervical ripening in women that undergo induction of labour by means of a vaginal prostaglandin slow-release delivery system (Propess®). Prospective ...observational study on 204 women that required induction of labour between February 2019 and May 2020 at "La Mancha Centro" hospital in Alcázar de San Juan, Spain. The main variable studied was effective cervical ripening (Bishop score > 6). Using multivariate analysis and binary logistic regression, we created three initial predictive models (model A: Bishop Score + Ultrasound cervical length + clinical variables (estimated fetal weight, premature rupture of membranes and body mass index)); model B: Ultrasound cervical lenght + clinical variables; and model C: Bishop score + clinical variables) to predict effective cervical ripening. All three predictive models obtained (A, B and C) presented good predictive capabilities, with an area under the ROC curve ≥ 0.76. Predictive model C, composed of the variables: gestational age (OR 1.55, 95% CI 1.18-2.03, p = 0.002), premature rupture of membranes (OR 3.21 95% CI 1.34-7.70, p = 0.09) body mass index (OR 0.93, 95% CI 0.87-0.98, p = 0.012), estimated fetal weight (OR 0.99, 95% CI 0.99-1.00, p = 0.068) and Bishop score (OR 1.49 95% CI 1.18-1.81, p = 0.001), is presented as the model of choice with an area under the ROC curve of 0.76 (95% CI 0.70-0.83, p < 0.001). A predictive model composed of the variables: gestational age, premature rupture of membranes, body mass index, estimated fetal weight and Bishop score upon admission presents good capabilities in predicting successful cervical ripening following administration of prostaglandins. This tool could be useful in making clinical decisions with regard to induction of labour.
Autophagy is a conserved pathway that maintains cellular quality control. Extracellular signal-regulated kinase (ERK) controls various aspects of cell physiology including proliferation. Multiple ...signalling cascades, including ERK, have been shown to regulate autophagy, however whether autophagy proteins (ATG) regulate cell signalling is unknown. Here we show that growth factor exposure increases the interaction of ERK cascade components with ATG proteins in the cytosol and nucleus. ERK and its upstream kinase MEK localize to the extra-luminal face of autophagosomes. ERK2 interacts with ATG proteins via its substrate-binding domains. Deleting Atg7 or Atg5 or blocking LC3 lipidation or ATG5-ATG12 conjugation decreases ERK phosphorylation. Conversely, increasing LC3-II availability by silencing the cysteine protease ATG4B or acute trehalose exposure increases ERK phosphorylation. Decreased ERK phosphorylation in Atg5⁻/⁻ cells does not occur from overactive phosphatases. Our findings thus reveal an unconventional function of ATG proteins as cellular scaffolds in the regulation of ERK phosphorylation.
The integrative physiology of inter-organ communication in lipophagy regulation is not well understood. Lipophagy and the cytosolic lipases ATGL and HSL contribute to lipid droplet (LD) mobilization; ...however, whether autophagy proteins engage with lipases to promote lipid utilization remains unknown. Here, we show that cold induces autophagy in proopiomelanocortin (POMC) neurons and activates lipophagy in brown adipose tissue (BAT) and liver in mice. Targeted activation of autophagy in POMC neurons via intra-hypothalamic rapamycin is sufficient to trigger lipid utilization in room temperature-housed mice. Conversely, inhibiting autophagy in POMC neurons or in peripheral tissues or denervating BAT blocks lipid utilization. Unexpectedly, the autophagosome marker LC3 is mechanistically coupled to ATGL-mediated lipolysis. ATGL exhibits LC3-interacting region (LIR) motifs, and mutating a single LIR motif on ATGL displaces ATGL from LD and disrupts lipolysis. Thus, cold-induced activation of central autophagy activates lipophagy and cytosolic lipases in a complementary manner to mediate lipolysis in peripheral tissues.
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•Cold induces autophagy in the hypothalamus and lipophagy in brown fat and liver•Stimulating hypothalamic autophagy activates lipophagy at ambient temperature•Inhibiting CNS or peripheral autophagy or denervating BAT blocks lipid utilization•Lipophagy and cytosolic lipases display complementarity toward total lipolysis
Martinez-Lopez et al. show that cold exposure induces autophagy in POMC neurons, which is necessary to activate lipophagy in brown adipose tissue and liver through the sympathetic network. Direct crosstalk between autophagy proteins and lipases in peripheral lipid droplets ensure maximal lipolysis rates
Macroautophagy (MA) regulates cellular quality control and energy balance. For example, loss of MA in aP2‐positive adipocytes converts white adipose tissue (WAT) into brown adipose tissue (BAT)‐like, ...enhancing BAT function and thereby insulin sensitivity. However, whether MA regulates early BAT development is unknown. We report that deleting Atg7 in myogenic Myf5+ progenitors inhibits MA in Myf5‐cell‐derived BAT and muscle. Knock out (KO) mice have defective BAT differentiation and function. Surprisingly, their body temperature is higher due to WAT lipolysis‐driven increases in fatty acid oxidation in ‘Beige’ cells in inguinal WAT, BAT and muscle. KO mice also present impaired muscle differentiation, reduced muscle mass and glucose intolerance. Our studies show that ATG7 in Myf5+ progenitors is required to maintain energy and glucose homeostasis through effects on BAT and muscle development. Decreased MA in myogenic progenitors with age and/or overnutrition might contribute to the metabolic defects and sarcopenia observed in these conditions.
Atg7 deletion in Myf5+ progenitors blocks autophagy in brown adipose tissue and muscle, affecting their differentiation and function. Knockout mice have higher body temperatures and glucose intolerance, underscoring the importance of autophagy in these processes.
Here, we present a technique for the determination of the gaseous oxygen concentration inside packed food. It is based on the use of a luminescent membrane sensitive to O 2 that is optically excited ...and read by a smartphone. The flash of the smartphone along with an optical filter is used as the light source for the optical stimulation of the membrane. The luminescence generated, which is quenched by the surrounding gaseous oxygen, is registered by the rear camera of the same device. The response parameter is defined by combining the registered intensities at two different wavelength ranges corresponding to the emission and the absorption peaks of the sensitive membrane. Thanks to this novel response parameter, the sensitivity is increased and, more importantly, the thermal dependence of the membrane is significantly reduced. This approach allows the use of a luminescent O 2 -sensitive membrane for intelligent packaging with no need of any associated electronics for its excitation and reading. This means that an oxygen sensor is developed, where a luminescent compound acts as an indicator, therefore combining the advantages of both schemes, that is, the simplicity and reduced cost of indicators with the high sensitivity and accuracy of selective sensors.
S‐adenosylmethionine (SAMe) is involved in numerous complex hepatic processes such as hepatocyte proliferation, death, inflammatory responses, and antioxidant defense. One of the most relevant ...actions of SAMe is the inhibition of hepatocyte proliferation during liver regeneration. In hepatocytes, SAMe regulates the levels of cytoplasmic HuR, an RNA‐binding protein that increases the half‐life of target messenger RNAs such as cyclin D1 and A2 via inhibition of hepatocyte growth factor (HGF)‐mediated adenosine monophosphate–activated protein kinase (AMPK) phosphorylation. Because AMPK is activated by the tumor suppressor kinase LKB1, and AMPK activates endothelial nitric oxide (NO) synthase (eNOS), and NO synthesis is of great importance for hepatocyte proliferation, we hypothesized that in hepatocytes HGF may induce the phosphorylation of LKB1, AMPK, and eNOS through a process regulated by SAMe, and that this cascade might be crucial for hepatocyte growth. We demonstrate that the proliferative response of hepatocytes involves eNOS phosphorylation via HGF‐mediated LKB1 and AMPK phosphorylation, and that this process is regulated by SAMe and NO. We also show that knockdown of LKB1, AMPK, or eNOS with specific interference RNA (iRNA) inhibits HGF‐mediated hepatocyte proliferation. Finally, we found that the LKB1/AMPK/eNOS cascade is activated during liver regeneration after partial hepatectomy and that this process is impaired in mice treated with SAMe before hepatectomy, in knockout mice deficient in hepatic SAMe, and in eNOS knockout mice. Conclusion: We have identified an LKB1/AMPK/eNOS cascade regulated by HGF, SAMe, and NO that functions as a critical determinant of hepatocyte proliferation during liver regeneration after partial hepatectomy. (HEPATOLOGY 2009;49:608–617.)
Vaginal dinoprostone (PGE
) is currently used as the prostaglandin of choice in many obstetric units. However, few studies have evaluated its safety, especially in women who previously had a cesarean ...section.
To evaluate the efficacy and safety of PGE
in pregnant women who are undergoing induction of labor (IOL), and who have had a previous cesarean section.
A prospective observational study was conducted in La Mancha Centro Hospital in Alcázar de San Juan, Spain, from 1 February 2019 to 30 August 2020. Obstetric and neonatal outcomes, following IOL with PGE
, in 47 pregnant women who wanted a trial of labor after cesarean (TOLAC), and 377 pregnant women without a history of cesarean section, were analyzed. The outcomes were analyzed by bivariate and multivariate analyses using binary and multiple linear regression.
A total of 424 women were included in this study. The percentage of cesarean sections in the TOLAC group was 44.7% (21), compared with 31.6% (119) in the group without a history of cesarean section (adjusted odds ratio: 1.4; 95% CI: 0.68-2.86). In the multivariate analysis, no statistically significant differences were observed between both groups for obstetric and neonatal outcomes (
> 0.05). However, two uterine ruptures (4.3%) occurred in the group of patients with a history of cesarean section who underwent IOL with PGE
.
The induction of labor with vaginal dinoprostone (PGE
), in patients with a previous history of cesarean section, was not associated with worse obstetric or neonatal outcomes compared with the group of patients without a history of cesarean section in our study sample. However, further research is needed regarding this IOL method, and it should be used with caution in this population group.
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