Mitochondrial carnitine palmitoyltransferase-II dysfunction: A possible novel mechanism for nonalcoholic fatty liver disease in hepatocarcinogenesis

Yao, Min; Zhou, Ping; Qin, Yanyan; Wang, Li; Yao, Dengfu

doi:10.3748/wjg.v29.i12.1765

Cited by 6 publications

(5 citation statements)

References 121 publications

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“…Carnitine metabolism is also shown to be altered at lines n. 15, 30, 38, 67, 78 and 81 in Table 1. Carnitines metabolism is mostly at the mitochondrial level and is crucial for the fatty acid oxidation and energy production [48][49][50][51], and carnitines are reported as key mitochondrial players in different pathologic conditions [50,[52][53][54][55][56]. The potential role carnitine-metabolism-related genes may play in melanoma growth was then confirmed by the analysis depicted in Table 2 and Figure 9, indicating significant expression change and significant correlation with survival in melanoma patients.…”

Section: Discussionmentioning

confidence: 74%

“…Polyamine, putrescin and asparagine metabolism are known to be strongly altered in cancer [59][60][61]. Metabolism of amino acids, polyamines, ornithine and taurine are all strongly inter-connected, and their expression was in fact found significantly altered in Table 1 (see lines n. 6,8,18,19,20,23,35,39,41,42,52,54,59 and 79) indicating a profound metabolism alteration of all amino acids and proteins. Finally, choline-related metabolism was found modified in Table 1 (see line n. 16, 57, 58, 60, 61, 63, 64, 65, 66 70, 71, 73, 74, 75 and 76), indicating a significant effect of miconazole on an essential molecule in phospholipids structure as well as in neurotransmitters, linked to betaine metabolism [62] and to fatty acids synthesis, which were in fact significantly modified in Table 1 at lines n. 12, 17, 38, 51, 82.…”

Section: Discussionmentioning

confidence: 99%

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Anti-Melanoma Effects of Miconazole: Investigating the Mitochondria Involvement

Scatozza,

Giardina,

Valente

et al. 2024

IJMS

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Miconazole is an antimycotic drug showing anti-cancer effects in several cancers. However, little is known on its effects in melanoma. A375 and SK-MEL-28 human melanoma cell lines were exposed to miconazole and clotrimazole (up to 100 mM). Proliferation, viability with MTT assay and vascular mimicry were assayed at 24 h treatment. Molecular effects were measured at 6 h, namely, ATP-, ROS-release and mitochondria-related cytofluorescence. A metabolomic profile was also investigated at 6 h treatment. Carnitine was one of the most affected metabolites; therefore, the expression of 29 genes involved in carnitine metabolism was investigated in the public platform GEPIA2 on 461 melanoma patients and 558 controls. After 24 h treatments, miconazole and clotrimazole strongly and significantly inhibited proliferation in the presence of 10% serum on either melanoma cell lines; they also strongly reduced viability and vascular mimicry. After 6 h treatment, ATP reduction and ROS increase were observed, as well as a significant reduction in mitochondria-related fluorescence. Further, in A375, miconazole strongly and significantly altered expression of several metabolites including carnitines, phosphatidyl-cholines, all amino acids and several other small molecules, mostly metabolized in mitochondria. The expression of 12 genes involved in carnitine metabolism was found significantly modified in melanoma patients, 6 showing a significant impact on patients’ survival. Finally, miconazole antiproliferation activity on A375 was found completely abrogated in the presence of carnitine, supporting a specific role of carnitine in melanoma protection toward miconazole effect, and was significantly reversed in the presence of caspases inhibitors such as ZVAD-FMK and Ac-DEVD-CHO, and a clear pro-apoptotic effect was observed in miconazole-treated cells, by FACS analysis of Annexin V-FITC stained cells. Miconazole strongly affects proliferation and other biological features in two human melanoma cell lines, as well as mitochondria-related functions such as ATP- and ROS-release, and the expression of several metabolites is largely dependent on mitochondria function. Miconazole, likely acting via carnitine and mitochondria-dependent apoptosis, is therefore suggested as a candidate for further investigations in melanoma treatments.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Anti-Melanoma Effects of Miconazole: Investigating the Mitochondria Involvement

Scatozza,

Giardina,

Valente

et al. 2024

IJMS

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“…These interactions make it more difficult to elucidate the functional influences that occur in both directions. As previously reported, 17β-hydroxysteroid dehydrogenases [ 50 ], the α1 subunit of Na + /K + -ATPase [ 51 ], carnitine palmitoyltransferase-II [ 52 ] and other targets are involved in those mechanisms. Functional validations are required to determine the role of microbes and their interactions with the host.…”

Section: Discussionmentioning

confidence: 80%

17β-Estradiol protects female rats from bilateral oophorectomy-induced nonalcoholic fatty liver disease induced by improving linoleic acid metabolism alteration and gut microbiota disturbance

Tian,

Xie,

Hong

et al. 2024

Heliyon

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“…Since ChREBP is a major modulator of hepatic triglyceride concentration through the regulation of lipogenesis and triglyceride synthesis, this represents the pathway for worsening insulin resistance due to hepatic lipid accumulation [85]. Another proposed mechanism is the reduced activity of hepatic carnitine palmitoyl transferases (CPTs), which are important for long-chain fatty acid (LCFA) oxidation since they are capable of being transported through the mitochondrial membrane [87]. Db/db mice with increased expression of CPT1A and CPT1AM were protected against obesity-induced weight gain, hepatic steatosis, and insulin resistance.…”

Section: Lipid Accumulation In the Liver And Insulin Resistancementioning

confidence: 99%

The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach

Vesković,

Šutulović,

Hrnčić

et al. 2023

CIMB

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The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1/PERK/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression.

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Mitochondrial carnitine palmitoyltransferase-II dysfunction: A possible novel mechanism for nonalcoholic fatty liver disease in hepatocarcinogenesis

Cited by 6 publications

References 121 publications

Anti-Melanoma Effects of Miconazole: Investigating the Mitochondria Involvement

Anti-Melanoma Effects of Miconazole: Investigating the Mitochondria Involvement

17β-Estradiol protects female rats from bilateral oophorectomy-induced nonalcoholic fatty liver disease induced by improving linoleic acid metabolism alteration and gut microbiota disturbance

The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach

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