Aging‐induced aberrant RAGE/PPARα axis promotes hepatic steatosis via dysfunctional mitochondrial β oxidation

Wan, Jian; Wu, Xiangsong; Chen, Hanbei; Xia, Xinyi; Su, Xi; Chen, Song; Lu, Xinyuan; Jin, Jie; Su, Qing; Cai, Dongsheng; Liu, Bin; Li, Bo

doi:10.1111/acel.13238

Cited by 32 publications

(32 citation statements)

References 57 publications

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“…Similar increase in lipid droplets were found in the liver of aging mice [21,31]. Interestingly, in Fischer 344 male rats the volume of lipid droplets in hepatocytes undergoes a biphasic response during aging, i.e.…”

Section: Discussionsupporting

confidence: 69%

Short-term fenofibrate treatment improves ultrastructure of hepatocytes of old rats

Zubrzycki

Wrońska

Zauszkiewicz-Pawlak

et al. 2021

Folia Histochem Cytobiol.

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Introduction. Fenofibrate (FN) is a hypolipemic drug used for the treatment of mixed dyslipidemia. Since in our previous study FN administration to young and old rats adversely affected the serum activity of liver marker enzymes, we decided to examine the effects of FN on liver ultrastructure of young and old animals.Material and methods. Young and old rats were fed standard rodent chow supplemented with 0.1% FN for 30 days. Liver samples obtained from animals under full anesthesia were processed by routine methods to obtain ultrathin and histological sections for the examination by light microscopy (LM) and transmission electron microscopy (TEM). Furthermore, liver lysates were analyzed by Western blotting for the expression of the autophagy-related proteins LC3A/B and beclin 1.Results. The ultrastructure of hepatocytes in both age groups was well-preserved, with the presence of abundant mitochondria, numerous peroxisomes and lysosomes, glycogen stored in the form of rosettes, and occasionally autolysosomes. However, hepatocytes of old control rats contained less mitochondria and peroxisomes, and more lipid droplets than cells of young animals. The effects of FN on liver ultrastructure were age-depended. FN increased the relative number of mitochondria and peroxisomes in the hepatocytes of old, and did not affect their number in young rats. Moreover, FN decreased and increased the relative number of lipid droplets in the hepatocytes of old and young rats, respectively. At the LM level, Oil Red O staining revealed smaller and larger lipid droplets within hepatocytes and non-parenchymal liver cells. In the livers of young and old rats lipid droplets were distributed mainly in the periportal zones of hepatic lobules. Morphometric analysis confirmed that livers of control old rats contained more lipid-stainable areas than those of young ones; however, no effect of FN was observed either in young or old rats. Despite larger size of autolysosomes and autophagic vacuoles in hepatocytes of old rats, the expression of autophagy-related proteins did not differ in the livers of control and fenofibrate-treated young and old animals. Conclusions.The results of our study suggest that fenofibrate, apart from its hypolipemic action, may have beneficial effect on the energy metabolism in the liver of old individuals by increasing the number of mitochondria and peroxisomes in hepatocytes.

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Section: Discussionsupporting

confidence: 69%

Short-term fenofibrate treatment improves ultrastructure of hepatocytes of old rats

Zubrzycki

Wrońska

Zauszkiewicz-Pawlak

et al. 2021

Folia Histochem Cytobiol.

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“…In the future 30 years, the aged group of population would occupy up to one‐fifth of the population 24 . Ageing is one of the strongest inducer in the decline of organ function 25,26 . However, the inducing factors of ageing have not been demonstrated in detail.…”

Section: Discussionmentioning

confidence: 99%

“…24 Ageing is one of the strongest inducer in the decline of organ function. 25 , 26 However, the inducing factors of ageing have not been demonstrated in detail. Among the multiple aetiologies of ageing, mitochondrial dysfunction is thought to be the very important mediator in acceleration of ageing and decline of organ function.…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid receptor 2 plays a central role in renal tubular mitochondrial dysfunction and kidney ageing

Zhou

Ling

Meng

et al. 2021

J Cellular Molecular Medi

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Kidney is one of the most important organs in maintaining the normal life activities. With the high abundance of mitochondria, renal tubular cell plays the vital role in functioning in the reabsorption and secretion of kidney. Reports have shown that mitochondrial dysfunction is of great importance to renal tubular cell senescence and subsequent kidney ageing. However, the underlying mechanisms are not elucidated. Cannabinoid receptor 2 is one of the two receptors responsible for the activation of endocannabinoid system. CB2 is primarily upregulated in renal tubular cells in chronic kidney diseases and mediates fibrogenesis. However, the role of CB2 in tubular mitochondrial dysfunction and kidney ageing has not been clarified. In this study, we found that CB2 was upregulated in kidneys in 24‐month‐old mice and d‐galactose (d‐gal)‐induced accelerated ageing mice, accompanied by the decrease in mitochondrial mass. Furthermore, gene deletion of CB2 in d‐gal‐treated mice could greatly inhibit the activation of β‐catenin signalling and restore the mitochondrial integrity and Adenosine triphosphate (ATP) production. In CB2 knockout mice, renal tubular cell senescence and kidney fibrosis were also significantly inhibited. CB2 overexpression or activation by the agonist AM1241 could sufficiently induce the decrease in PGC‐1α and a variety of mitochondria‐related proteins and trigger cellular senescence in cultured human renal proximal tubular cells. CB2‐activated mitochondrial dysfunction and cellular senescence could be blocked by ICG‐001, a blocker for β‐catenin signalling. These results show CB2 plays a central role in renal tubular mitochondrial dysfunction and kidney ageing. The intrinsic mechanism may be related to its activation in β‐catenin signalling.

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“…The mechanisms underlying ageing process involve many genetic, biochemical, physiological, nutritional and environmental factors and their interactions. During the ageing process, abnormal lipid metabolism and energy metabolism are one of the important alterations of many biochemical and physiological parameters 31 . In the present study, we examined the effects of AST on biochemical and physiological parameters related to lipid metabolism pathways and the enzymes/proteins involved in these pathways, including fatty acid biosynthesis and fatty acid β‐oxidation, KB production, mitochondrial electron transport chain (ETC) and mitochondrial biosynthesis capacity in hepatocytes and liver of ageing mice.…”

Section: Discussionmentioning

confidence: 99%

“…During the ageing process, abnormal lipid metabolism and energy metabolism are one of the important alterations of many biochemical and physiological parameters. 31 In the present study, we examined the effects of AST on biochemical and physiological parameters related to lipid metabolism pathways and the enzymes/proteins involved in these pathways, including fatty acid biosynthesis and fatty acid β‐oxidation, KB production, mitochondrial electron transport chain (ETC) and mitochondrial biosynthesis capacity in hepatocytes and liver of ageing mice. Our results indicate that AST administration stimulated FAO and KB production by up‐regulation of the key enzymes/proteins involved in these two processes and inhibited fatty acid biosynthesis by down‐regulating the enzymes/proteins involved in this pathway.…”

Section: Discussionmentioning

confidence: 99%

Astragaloside IV ameliorates fat metabolism in the liver of ageing mice through targeting mitochondrial activity

Luo

Wang

Xue

et al. 2021

J Cellular Molecular Medi

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Astragaloside IV (AST) is a major bioactive compound of Radix Astragali with medical and health benefits. Previous studies have found that AST can reduce the body weights of high‐fat diet fed mice. However, the effect of AST on fat metabolism of ageing mice is unclear. In this study, naturally ageing mice were administered intragastrically with AST at 30 mg/kg/day (ageing + AST‐L group) and 90 mg/kg/day (ageing + AST‐H group) for 16–20 months. Adult (4 months old) and ageing mice were given 1% sodium carboxyl methylcellulose as vehicle. Energy metabolism‐related biological parameters of living mice were examined. Moreover, mRNA and protein levels of key enzymes/proteins involved in triglyceride (TG) lipolysis, fatty acid β‐oxidation (FAO), ketone body (KB) production and mitochondrial respiratory chain were also examined after sacrifice. Results demonstrated that treatment with AST significantly reduced body weight, white fat and liver/body weight ratio of ageing mice, significantly reduced serum/hepatic TG levels, respiratory quotient, promoted fatty acid mobilization in white adipose tissue, mitochondrial FAO and KB production and mitochondrial biosynthesis/functions in the liver of ageing mice. AST also up‐regulated the expression of phosphorylated AMP‐activated protein kinase, acetyl‐CoA carboxylase, acetyl‐coenzyme A synthetase, carnitine palmitoyltransferase 1a/1b, enoyl coenzyme A hydratase‐short chain, acyl‐CoA dehydrogenase medium chain and mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase‐2 involved in fat metabolism. These results indicated that mitochondrial activity could be the target of AST to treat abnormal fat metabolism during ageing.

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Aging‐induced aberrant RAGE/PPARα axis promotes hepatic steatosis via dysfunctional mitochondrial β oxidation

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 32 publications

References 57 publications

Short-term fenofibrate treatment improves ultrastructure of hepatocytes of old rats

Short-term fenofibrate treatment improves ultrastructure of hepatocytes of old rats

Cannabinoid receptor 2 plays a central role in renal tubular mitochondrial dysfunction and kidney ageing

Astragaloside IV ameliorates fat metabolism in the liver of ageing mice through targeting mitochondrial activity

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