AMPK activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation

Herms, Albert; Bosch, Marta; Reddy, Babu J.N.; Schieber, Nicole L.; Fajardo, Alba; Rupérez, Celia; Fernández-Vidal, Andrea; Ferguson, Charles; Rentero, Carles; Tebar, Francesc; Enrich, Carlos; Parton, Robert G.; Gross, Steven P.; Pol, Albert

doi:10.1038/ncomms8176

Cited by 234 publications

(263 citation statements)

References 55 publications

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“…In addition to decreased movement of degradative compartments along the microtubule network, the effects of EtOH are likely to inhibit motility of LDs themselves, organelles also known to exhibit direct links to the microtubule network. In fact, nutrient limitation was shown to promote LD dispersion along detyrosinated microtubules to the cell periphery, promoting interactions between the LD and mitochondria for β‐oxidation 38. Proteins regulating the movement of LDs are only now beginning to be understood.…”

Section: Discussionmentioning

confidence: 99%

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Schulze¹,

Rasineni

Weller³

et al. 2017

Hepatology Communications

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Alcohol consumption is a well‐established risk factor for the onset and progression of fatty liver disease. An estimated 90% of heavy drinkers are thought to develop significant liver steatosis. For these reasons, an increased understanding of the molecular basis for alcohol‐induced hepatic steatosis is important. It has become clear that autophagy, a catabolic process of intracellular degradation and recycling, plays a key role in hepatic lipid metabolism. We have shown that Rab7, a small guanosine triphosphatase known to regulate membrane trafficking, acts as a key orchestrator of hepatocellular lipophagy, a selective form of autophagy in which lipid droplets (LDs) are specifically targeted for turnover by the autophagic machinery. Nutrient starvation results in Rab7 activation on the surface of the LD and lysosomal compartments, resulting in the mobilization of triglycerides stored within the LDs for energy production. Here, we examine whether the steatotic effects of alcohol exposure are a result of perturbations to the Rab7‐mediated lipophagic pathway. Rats chronically fed an ethanol‐containing diet accumulated significantly higher levels of fat in their hepatocytes. Interestingly, hepatocytes isolated from these ethanol‐fed rats contained juxtanuclear lysosomes that exhibited impaired motility. These changes are similar to those we observed in Rab7‐depleted hepatocytes. Consistent with these defects in the lysosomal compartment, we observed a marked 80% reduction in Rab7 activity in cultured hepatocytes as well as a complete block in starvation‐induced Rab7 activation in primary hepatocytes isolated from chronic ethanol‐fed animals. Conclusion: A mechanism is supported whereby ethanol exposure inhibits Rab7 activity, resulting in the impaired transport, targeting, and fusion of the autophagic machinery with LDs, leading to an accumulation of hepatocellular lipids and hepatic steatosis. (Hepatology Communications 2017;1:140‐152)

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Section: Discussionmentioning

confidence: 99%

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Schulze¹,

Rasineni

Weller³

et al. 2017

Hepatology Communications

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“…It has previously been reported that LU can activate AMPK signalling in differentiated 3T3-L1 adipocytes [24] and HepG2 hepatocytes [23]. In addition, AMPK, as an important nutrient sensor, can promote fatty acid oxidation [37] and energy expenditure [38]. Indeed, in the HFD + LU20 group, dietary LU not only suppressed EAT macrophage polarisation (Fig.…”

Section: Discussionmentioning

confidence: 75%

Luteolin reduces obesity-associated insulin resistance in mice by activating AMPKα1 signalling in adipose tissue macrophages

et al. 2016

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Aims/hypothesis Inflammatory polarisation of adipose tissue macrophages (ATMs) plays a critical role in the development of obesity-associated metabolic diseases such as insulin resistance and diabetes. Our previous study indicated that dietary luteolin (LU) could prevent the establishment of insulin resistance in mice fed a high-fat diet (HFD). Here, we further investigated the effects of LU, which is a natural flavonoid, on pre-established insulin resistance and obesityassociated ATM polarisation in mice. Methods Five-week-old C57/BL6 mice were fed on a low-fat diet or HFD for 20 weeks, with some mice receiving supplementation with 0.01% LU from weeks 1 or 10 of the HFD to assess the actions of LU on insulin resistance and ATM polarisation. Furthermore, the role of LU in metabolicdysfunction-associated macrophage phenotypes was investigated in vitro. Results Dietary LU supplementation, either for 20 weeks or from weeks 10 to 20 of an HFD, significantly improved insulin resistance in HFD-fed mice. In addition, inflammatory macrophage infiltration and polarisation were suppressed in mouse epididymal adipose tissues. Furthermore, LU treatment directly reversed lipopolysaccharide-stimulated and metabolism-regulated molecules, and induced inflammatory polarisation in mouse RAW264.7 cells and peritoneal cavity resident macrophages. Finally, using the selective AMPactivated protein kinase (AMPK) inhibitor compound C and Ampkα1 (also known as Prkaa1) silencing with siRNA, we found that LU activated AMPKα1 in macrophages to inhibit their inflammatory polarisation and enhanced insulin signals in adipocytes that were stimulated with macrophageconditioned media. Conclusions/interpretation Dietary LU ameliorated insulin resistance in diet-induced obese mice by promoting AMPKα1 signalling in ATMs.

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“…In glioma cells, inhibition of fatty acid oxidation caused significant reduction of NADPH, accumulation of redox oxygen species, and eventually cell death [85]. The involved mechanisms of NADPH production by fatty acid oxidation were later found to be mediated by LKB1-AMPK pathway [86,87]. Lastly, one study demonstrated that leukemia progenitor cells required fatty acid oxidation to maintain stem cell property [88].…”

Section: Lipid Catabolism In Liver Cancer: a Potential Therapeutic Tamentioning

confidence: 99%

Lipid Metabolism in Liver Cancer

Lu¹,

Hooi²

2017

Updates in Liver Cancer

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Hepatocellular carcinoma (HCC) represents 90% cases of liver cancer that is the second leading cause of cancer death in the world. With the pandemic of obesity and other metabolic syndromes in both adults and children, the incidences of fatty liver diseases and the derived HCC are on their upward track. Emerging metabolomic studies have revealed the perturbation of lipid profiles and other metabolites in fatty liver diseases and HCC. Two common metabolic features including enforced fatty acid oxidation and glycolysis could distinguish HCC from healthy liver and chronic non-tumor liver diseases. The potential translational impacts of fatty acid oxidation are gaining great interests, because many recent investigations have demonstrated that tumor cells were dependent on fatty acid oxidation for cell survival and tumor growth. Blockage of fatty acid oxidation could sensitize to metabolic stress-induced cell death and tumor growth inhibition. Thus, lipid catabolism, in terms of fatty oxidation, is tuned for tumor maintenance but vulnerable to pharmacological disruption. The therapeutic potentials of blocking fatty acid oxidation are yet to be further carefully examined.

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AMPK activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation

Cited by 234 publications

References 55 publications

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Luteolin reduces obesity-associated insulin resistance in mice by activating AMPKα1 signalling in adipose tissue macrophages

Lipid Metabolism in Liver Cancer

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