Coenzyme Q10 Improves Lipid Metabolism and Ameliorates Obesity by Regulating CaMKII-Mediated PDE4 Inhibition

Xu, Zhe; Huo, Jia; Ding, Xiaoyan; Mi, Yang; Li, Lin; Dai, Jian; Hosoe, Kazunori; Kubo, Hiroshi; Mori, Masayuki; Higuchi, Kenichi; Sawashita, Jinko

doi:10.1038/s41598-017-08899-7

Cited by 88 publications

(62 citation statements)

References 74 publications

(74 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Importantly, resveratrol has been demonstrated to increase cAMP by inhibiting PDE4 [67]. A recent study also reported that dietary supplementation of a reduced form of coenzyme Q10 (CoQ 10 H 2 ) suppressed hepatic PDE4 expression, increased cAMP levels and fatty acid β-oxidation via the SIRT-1/PGC-1α/PPARα pathway, and inhibited the development and progression of obesity and type 2 diabetes in a mouse model [68]. The authors also reported the inhibitory effect of CoQ 10 H 2 on the genes involved in de novo lipogenesis in the liver such as SREBP1c.…”

Section: The Role Of Camp In Nafldmentioning

confidence: 99%

Role of cAMP and phosphodiesterase signaling in liver health and disease

Wahlang

McClain

Barve

et al. 2018

Cellular Signalling

103

View full text Add to dashboard Cite

Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.

show abstract

Section: The Role Of Camp In Nafldmentioning

confidence: 99%

Role of cAMP and phosphodiesterase signaling in liver health and disease

Wahlang

McClain

Barve

et al. 2018

Cellular Signalling

103

View full text Add to dashboard Cite

show abstract

“…We next tested whether CoQ could alleviate insulin resistance in vivo by providing liposomal CoQ 10 via intraperitoneal injection every second day. CoQ 10 was used for these studies as it was not feasible to obtain sufficient CoQ 9 and the doses of CoQ 10 used in these studies were optimised so that we did not observe changes in body weight or adiposity, reported previously ( Xu et al, 2017 ), since such metabolic changes would likely directly affect insulin action in muscle and adipose. CoQ 10 administration improved whole-body glucose tolerance in mice fed a HFHSD for 5 or 14 d ( Figure 4D–E , Figure 4—figure supplement 1F–G ) without altering insulin secretion ( Figure 4F , Figure 4—figure supplement 1H ).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance

Fazakerley

Chaudhuri

Yang

et al. 2018

eLife

107

110

View full text Add to dashboard Cite

Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance.

show abstract

“…Ma et al also showed that treatment of baicalin, a flavone, causes an increase in [Ca 2+ ]i concentration at the similar amount to our result, which activated CaMKKβ in LKB1 deficient HeLa and A549 cell line 33 . In contrast, increased [Ca 2+ ]i can also activate other protein kinases, which potentially affect apoptosis and autophagy of GECs and podocytes related to endoplasmic reticulum stress and mitochondrial dysfunction, such as calcium/calmodulin dependent protein kinase II 34 . The precise mechanism underlying CaSR upregulation by cinacalcet and subsequent CaMKKβ/LKB1 activation is not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Cinacalcet-mediated activation of the CaMKKβ-LKB1-AMPK pathway attenuates diabetic nephropathy in db/db mice by modulation of apoptosis and autophagy

Lim

Kim

et al. 2018

Cell Death Dis

View full text Add to dashboard Cite

Apoptosis and autophagy are harmoniously regulated biological processes for maintaining tissue homeostasis. AMP-activated protein kinase (AMPK) functions as a metabolic sensor to coordinate cellular survival and function in various organs, including the kidney. We investigated the renoprotective effects of cinacalcet in high-glucose treated human glomerular endothelial cells (HGECs), murine podocytes and C57BLKS/J-db/db mice. In cultured HGECs and podocytes, cinacalcet decreased oxidative stress and apoptosis and increased autophagy that were attributed to the increment of intracellular Ca2+ concentration and the phosphorylation of Ca2+/calmodulin-dependent protein kinase kinaseβ (CaMKKβ)-Liver kinase B1 (LKB1)-AMPK and their downstream signals including the phosphorylation of endothelial nitric oxide synthase (eNOS) and increases in superoxide dismutases and B cell leukemia/lymphoma 2/BCL-2-associated X protein expression. Interestingly, intracellular chelator BAPTA-AM reversed cinacalcet-induced CaMKKβ elevation and LKB1 phosphorylation. Cinacalcet reduced albuminuria without influencing either blood glucose or Ca2+ concentration and ameliorated diabetes-induced renal damage, which were related to the increased expression of calcium-sensing receptor and the phosphorylation of CaMKKβ-LKB1. Subsequent activation of AMPK was followed by the activation of peroxisome proliferator-activated receptor γ coactivator-1α and phospho-Ser1177eNOS-nitric oxide, resulting in a decrease in apoptosis and oxidative stress as well as an increase in autophagy.Our results suggest that cinacalcet increases intracellular Ca2+ followed by an activation of CaMKKβ-LKB1-AMPK signaling in GECs and podocytes in the kidney, which provides a novel therapeutic means for type 2 diabetic nephropathy by modulation of apoptosis and autophagy.

show abstract

Coenzyme Q10 Improves Lipid Metabolism and Ameliorates Obesity by Regulating CaMKII-Mediated PDE4 Inhibition

Cited by 88 publications

References 74 publications

Role of cAMP and phosphodiesterase signaling in liver health and disease

Role of cAMP and phosphodiesterase signaling in liver health and disease

Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance

Cinacalcet-mediated activation of the CaMKKβ-LKB1-AMPK pathway attenuates diabetic nephropathy in db/db mice by modulation of apoptosis and autophagy

Contact Info

Product

Resources

About