Aging exacerbates high‐fat diet‐induced steatohepatitis through alteration in hepatic lipid metabolism in mice

Ishizuka, Kei; Kon, Kazuyoshi; Lee-Okada, Hyeon-Cheol; Arai, Kumiko; Uchiyama, Akira; Yamashina, Shunhei; Yokomizo, Takehiko; Ikejima, Kenichi

doi:10.1111/jgh.15006

Cited by 12 publications

(9 citation statements)

References 41 publications

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“…This is supported by the observation that plasma levels of GLA, DGLA, AA, EPA and DHA are low in those with rheumatoid arthritis, lupus, and sepsis [103][104][105][106] (see Table 3). Aging is associated with decreased activities of desaturases and low plasma concentrations of LXA4 [107][108][109][110]. Based on these results, it is imperative to suggest that administration of GLA/DGLA/AA/EPA/DHA and their anti-inflammatory metabolites LXA4, resolvins, protectins and maresins or their stable and orally active synthetic molecules could be of benefit in inflammatory conditions and potentially to arrest aging process.…”

Section: M1 and M2 Macrophages And Bioactive Lipidsmentioning

confidence: 99%

“Cell Membrane Theory of Senescence” and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications

Das

2021

Biomolecules

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Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA and DHA and their metabolites. LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA and DHA noted in these conditions are due to the decreased activity of desaturases and elongases. PUFAs stimulate SIRT1 through protein kinase A-dependent activation of SIRT1-PGC1α complex and thus, increase rates of fatty acid oxidation and prevent lipid dysregulation associated with aging. SIRT1 activation prevents aging. Of all the SIRTs, SIRT6 is critical for intermediary metabolism and genomic stability. SIRT6-deficient mice show shortened lifespan, defects in DNA repair and have a high incidence of cancer due to oncogene activation. SIRT6 overexpression lowers LDL and triglyceride level, improves glucose tolerance, and increases lifespan of mice in addition to its anti-inflammatory effects at the transcriptional level. PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs (SIRt1 SIRT2, SIRT3, SIRT4, SIRT5, SIRT6), PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α). This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-, 12-, 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities.

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Section: M1 and M2 Macrophages And Bioactive Lipidsmentioning

confidence: 99%

“Cell Membrane Theory of Senescence” and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications

Das

2021

Biomolecules

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“…In addition, the inhibition of SIRT1 in Kupffer cells was related to a marked increase in the acetylation of NF-κB, which leads to inflammation of ALD Chronic inflammation acts as a widely recognized hallmark in ageing process [80,81]. Accumulating studies have proved that SIRT1 involved in many biological processes through regulating protein acetylation, thus, promotes longevity [82,83]. Previous studies researched that hepatic expression of SIRT1 protein was downregulated in the middle-aged mice compared to young mice, which lead to more liver injury and inflammation induced by ethanol feeding in middle-aged mice and aged mice when compared to young [84].…”

Section: Figure 2 the Roles Of Sirt1 In The Pathogenesis Of Alcoholic Steatosis And Inflammationmentioning

confidence: 99%

Emerging Roles of SIRT1 in Alcoholic Liver Disease

Ren¹,

Wang²,

Wu³

et al. 2020

Int. J. Biol. Sci.

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Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease worldwide with a wide spectrum of liver pathologies ranging from simple steatosis to steatohepatitis, cirrhosis, and even hepatocellular carcinoma. It has been demonstrated that ALD is mediated in whole or in part by a central signaling molecule sirtuin 1 (SIRT1), a conserved class III histone deacetylase.SIRT1 plays beneficial roles in regulating hepatic lipid metabolism, inhibiting hepatic inflammation, controlling hepatic fibrosis and mediating hepatocellular carcinoma in ALD. However, underlying molecular mechanisms are complex and remain incompletely understood. The aim of this review was to highlight the latest advances in understanding of SIRT1 regulatory mechanisms in ALD and discuss their unique potential role as novel therapeutic target for ALD treatment.

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“…Using p16 as a marker for senescent cells, these cells were isolated, and specific removal of senescent cells in NAFLD/NASH mouse models resulted in improved hepatic disease states 20,21 . A study comparing young and elderly mice demonstrated that aging exacerbates steatohepatitis due to alterations in hepatic lipid metabolism; elderly mice fed a high‐fat diet exhibited severe steatohepatitis and lipotoxicity, increased inflammation, and enhanced oxidative stress in the liver 22 . Consistent with the results of the aforementioned study, our study indicated that aged mice fed NASH‐inducing diet showed exacerbated steatohepatitis and fibrosis and enhanced oxidative stress in the liver compared with non‐aged mice.…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle atrophy is exacerbated by steatotic and fibrotic liver‐derived TNF‐α in senescence‐accelerated mice

Shirakami

Kato

Maeda

et al. 2023

J of Gastro and Hepatol

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Although liver diseases, including non-alcoholic steatohepatitis (NASH), are associated with skeletal muscle atrophy, the mechanism behind their association has not been fully elucidated. In this study, the effects of aging and NASH on the skeletal muscle and the interaction between the liver and muscle were investigated using a diet-induced NASH model in senescence-accelerated mice (SAM). A total of four groups of SAM and its control mice were fed either an NASH-inducing or control diet. In the SAM/NASH group, the histopathology of NASH and markers of oxidative stress were signi cant. Skeletal muscles were also markedly atrophied. The expression of the ubiquitin ligase Murf1 in the muscle was signi cantly increased with muscle atrophy, while that of Tnfa was not signi cantly different. In contrast, the hepatic Tnfa expression and serum TNF-α levels were signi cantly increased in the SAM/NASH group. These results suggest that liver-derived TNF-α might promote muscle atrophy associated with steatohepatitis and aging through Murf-1. The metabolomic analysis of skeletal muscle indicated higher spermidine and lower tryptophan levels in the NASH-diet group. The ndings of this study revealed an aspect of liver-muscle interaction, which might be important in developing treatments for sarcopenia associated with liver diseases.

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Aging exacerbates high‐fat diet‐induced steatohepatitis through alteration in hepatic lipid metabolism in mice

Cited by 12 publications

References 41 publications

“Cell Membrane Theory of Senescence” and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications

“Cell Membrane Theory of Senescence” and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications

Emerging Roles of SIRT1 in Alcoholic Liver Disease

Skeletal muscle atrophy is exacerbated by steatotic and fibrotic liver‐derived TNF‐α in senescence‐accelerated mice

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