Role of HO-1 against Saturated Fatty Acid-Induced Oxidative Stress in Hepatocytes

Ogino, Noriyoshi; Miyagawa, Koichiro; Nagaoka, Kenjiro; Matsuura-Harada, Yuki; Ogino, Shihona; Kusanaga, Masashi; Oe, Shinji; Honma, Yuichi; Harada, Masaru; Eitoku, Masamitsu; Suganuma, Narufumi; Oginö, Kazuhíde

doi:10.3390/nu13030993

Cited by 8 publications

(4 citation statements)

References 38 publications

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“…Decreased hepatic HO-1 expression was reported to improve oxidative stress in the liver and ameliorate the development of NAFLD. 40,41 Importantly, our findings showed that Britanin inhibited oxidative stress by downregulating the level of HO-1 expression. Moreover, the AMPK/SREBP1c pathway that is correlated with lipid metabolism was shown to participate in the Britanin-provided alleviation on NAFLD.…”

Section: ■ Discussionmentioning

confidence: 57%

Integrated Pharmaco-Bioinformatics Approaches and Experimental Verification To Explore the Effect of Britanin on Nonalcoholic Fatty Liver Disease

Dou,

Zhu,

Xie

et al. 2024

ACS Omega

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Nonalcoholic fatty liver disease (NAFLD) is a prevalent global liver disorder, posing substantial health risks. Britanin, a bioactive sesquiterpene lactone extracted from Inula japonica, has demonstrated antidiabetic, hypolipidemic, and hepatoprotective attributes. Nonetheless, the precise impact of Britanin on NAFLD and the intricate biological mechanisms underpinning this interaction remain unexplored. We integrated computer-aided methods to unearth shared biological targets and signaling pathways associated with both Britanin and NAFLD. A network was constructed by compiling putative targets associated with Britanin and NAFLD, followed by a stringent screening of key targets and mechanisms through protein–protein interaction analysis along with GO and KEGG pathway enrichment analyses. Molecular docking was integrated as an evaluation tool, culminating in the identification of HO-1 as the pivotal therapeutic target, showcasing a satisfactory binding affinity. The primary mechanism was ascribed to biological processes and pathways linked to oxidative stress, as evidenced by the outcomes of enrichment analyses. Of these, the AMPK/SREBP1c pathway assumed centrality in this mechanism. Furthermore, in vivo experiments substantiated that Britanin effectively curtailed NAFLD development by ameliorating liver injury, modulating hyperlipidemia and hepatic lipid accumulation, and alleviating oxidative stress and apoptosis. In summary, this study demonstrates the potential of Britanin as a promising therapeutic drug against NAFLD.

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Section: ■ Discussionmentioning

confidence: 57%

Integrated Pharmaco-Bioinformatics Approaches and Experimental Verification To Explore the Effect of Britanin on Nonalcoholic Fatty Liver Disease

Dou,

Zhu,

Xie

et al. 2024

ACS Omega

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“…SFAs such as palmitic acid suppress autophagy in hepatocytes, decreasing the levels of Nrf2, inducing ferroptosis of hepatocytes 39,40 . In a similar manner, excess intake of dietary SFA may promote ferroptosis of melanocytes in patients with vitiligo.…”

Section: Discussionmentioning

confidence: 98%

Dietary habits in adult Japanese patients with vitiligo

Hamada,

Funasaka,

Saeki

et al. 2024

The Journal of Dermatology

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Vitiligo is an autoimmune skin disease with acquired depigmentation. Dietary habits may modulate the pathogenesis of vitiligo. We evaluated dietary habits in adult Japanese patients with nonsegmental vitiligo, and compared their results with those of age‐ and sex‐matched controls. We also examined the relationship between dietary habits and Vitiligo Area Scoring Index (VASI), or vitiligo on different anatomical sites. The intakes of energy, nutrients, and foods in the participants were analyzed using a brief‐type self‐administered diet history questionnaire. Patients with vitiligo showed higher body mass index (BMI) and lower intakes of manganese, vitamin D, pulses, and confection, compared with controls. Multivariate logistic regression analysis showed that vitiligo was associated with high BMI. VASI was higher in males than in females, and negatively correlated with age or intakes of potatoes and vegetables other than green/yellow vegetables. Linear multivariate regression analysis showed that high VASI was associated with younger age. Multivariate logistic regression analysis showed that moderate to severe vitiligo (VASI ≥ 4.25) was associated with male sex and longer disease duration. Multivariate logistic regression analyses showed the following association with vitiligo on respective anatomical sites: high intake of eggs and dairy products and high VASI on the head or neck, high intake of oils and fats and high VASI on the trunk, high intake of cereals and high VASI on the upper limbs, male sex and high VASI on the lower limbs, and high BMI and high VASI on the hands or feet. In conclusion, the control of obesity might have prophylactic or therapeutic effects on vitiligo.

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“…Recently, Zeng et al demonstrated that increased levels of PA at the expense of OA are responsible for inflammasome and GSDMD activation, leading to pyroptosis-mediated cell death [ 12 ]. However, Akazawa and Nakao, as well as other groups, independently reported that high PA levels induce phospho-RIP-1-mediated necroptosis [ 10 , 18 , 19 ] with a promotion of mitochondrial ROS that allows the auto-phosphorylation of RIP-1 [ 20 , 21 ]. In addition, although several studies have demonstrated the toxicity of exosomes carrying PA, no studies have yet been conducted on the balance between PA and OA within the exosomes, and hence on their ratio, as the crucial player in the cell death event, rather than the individual exosome fatty level.…”

Section: Introductionmentioning

confidence: 99%

The oleic/palmitic acid imbalance in exosomes isolated from NAFLD patients induces necroptosis of liver cells via the elongase-6/RIP-1 pathway

Scavo,

Negro,

Arrè

et al. 2023

Cell Death Dis

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Excessive toxic lipid accumulation in hepatocytes underlies the development of non-alcoholic fatty liver disease (NAFLD), phenotypically characterized by necrosis and steato-fibrosis, whose molecular mechanism is not yet fully understood. Patients with NAFLD display an imbalanced palmitic (PA) to oleic acid (OA) ratio. Moreover, increasing experimental evidence points out a relevant involvement of the exosomal content in disease progression. Aim of the study was to highlight the PA/OA imbalance within circulating exosomes, the subsequent intracellular alterations, and the impact on NALFD. Liver cells were challenged with exosomes isolated from both healthy subjects and NAFLD patients. The exosomal PA/OA ratio was artificially modified, and biological effects were evaluated. A NAFLD-derived exosomal PA/OA imbalance impacts liver cell cycle and cell viability. OA-modified NAFLD-derived exosomes restored cellular viability and proliferation, whereas the inclusion of PA into healthy subjects-derived exosomes negatively affected cell viability. Moreover, while OA reduced the phosphorylation and activation of the necroptosis marker, Receptor-interacting protein 1 (phospho-RIP-1), PA induced the opposite outcome, alongside increased levels of stress fibers, such as vimentin and fibronectin. Administration of NAFLD-derived exosomes led to increased expression of Elongase 6 (ELOVL6), Stearoyl-CoA desaturase 1 (SCD1), Tumor necrosis factor α (TNF-α), Mixed-lineage-kinase-domain-like-protein (MLKL) and RIP-1 in the hepatocytes, comparable to mRNA levels in the hepatocytes of NAFLD patients reported in the Gene Expression Omnibus (GEO) database. Genetic and pharmacological abrogation of ELOVL6 elicited a reduced expression of downstream molecules TNF-α, phospho-RIP-1, and phospho-MLKL upon administration of NAFLD-derived exosomes. Lastly, mice fed with high-fat diet exhibited higher phospho-RIP-1 than mice fed with control diet. Targeting the Elongase 6–RIP-1 signaling pathway offers a novel therapeutic approach for the treatment of the NALFD-induced exosomal PA/OA imbalance.

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Role of HO-1 against Saturated Fatty Acid-Induced Oxidative Stress in Hepatocytes

Cited by 8 publications

References 38 publications

Integrated Pharmaco-Bioinformatics Approaches and Experimental Verification To Explore the Effect of Britanin on Nonalcoholic Fatty Liver Disease

Integrated Pharmaco-Bioinformatics Approaches and Experimental Verification To Explore the Effect of Britanin on Nonalcoholic Fatty Liver Disease

Dietary habits in adult Japanese patients with vitiligo

The oleic/palmitic acid imbalance in exosomes isolated from NAFLD patients induces necroptosis of liver cells via the elongase-6/RIP-1 pathway

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