Suppression of nitric oxide synthase aggravates non-alcoholic steatohepatitis and atherosclerosis in SHRSP5/Dmcr rat via acceleration of abnormal lipid metabolism

Sato, Ikumi; Yamamoto, Sadaki; Kakimoto, M.; Fujii, Moe; Honma, Koki; Kumazaki, Shota; Matsui, Mami; Nakayama, Hinako; Kirihara, Sora; Ran, Shang; Usui, Shinichi; Shinohata, Ryoko; Kitamori, Kazuya; Hirohata, Satoshi; Watanabe, Shozo

doi:10.1007/s43440-022-00380-1

Cited by 5 publications

(5 citation statements)

References 53 publications

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“…Obesity-induced oxidative stress impairs the nitric oxide (NO)-guanylyl cyclase pathway, and reduced NO synthesis aggravates liver steatosis and fat metabolism [39,40]. NO is produced from L-arginine via the L-arginine-NO synthase pathway.…”

Section: Discussionmentioning

confidence: 99%

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Oral L-Citrulline Supplementation Improves Fatty Liver and Dyslipidemia in Adolescents with Abdominal Obesity: A Parallel, Double-Blind, Randomized Clinical Trial

Tovar-Villegas,

Kang,

Ibarra-Reynoso

et al. 2024

Gastroenterology Insights

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Obesity in adolescents is associated with non-communicable risk factors and diseases like metabolic-associated fatty liver disease (MAFLD), which is the liver manifestation of metabolic syndrome. L-citrulline is a non-protein amino acid that has shown positive effects on the degree of steatosis in animals with non-alcoholic fatty liver disease (NAFLD). The aim of the study was to evaluate the effect of oral L-citrulline supplementation on liver function and cardiovascular risk factors in adolescents with abdominal obesity and MAFLD. A prospective, double-blind clinical trial in adolescents with abdominal obesity was randomized into two groups: forty-two adolescents were supplemented with L-citrulline (6 g of L-citrulline/day) (n = 22) and placebo (n = 20) for eight weeks. The variables evaluated were anthropometry, blood pressure, glucose, insulin, HOMA-IR, L-citrulline, L-arginine, malondialdehyde, lipid profile, liver profile, urea, uric acid, and hepatic steatosis by ultrasound. After supplementation, the L-citrulline group had a decrease in liver fat accumulation (p = 0.0007); increases in body weight (p = 0.02), glucose (p = 0.03), and HOMA-IR (p = 0.03); and decreases in BMI (p = 0.002), total cholesterol (p = 0.001), HDL-C (p = 0.01), LDL-C (p = 0.002), and alkaline phosphatase (p = 0.05). L-citrulline for eight weeks decreases hepatic fat accumulation and LDL-C levels in adolescents with abdominal obesity and MAFLD.

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Section: Discussionmentioning

confidence: 99%

“…The attenuation of liver steatosis may be associated with the lipolytic effect of L-citrulline observed on visceral fat in rats [44]. Thus, increased NO production would reduce liver steatosis by improving fat metabolism [39,40].…”

Section: Discussionmentioning

confidence: 99%

Oral L-Citrulline Supplementation Improves Fatty Liver and Dyslipidemia in Adolescents with Abdominal Obesity: A Parallel, Double-Blind, Randomized Clinical Trial

Tovar-Villegas,

Kang,

Ibarra-Reynoso

et al. 2024

Gastroenterology Insights

View full text Add to dashboard Cite

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“…Endothelium-derived NO exerts antioxidant and antiapoptotic efects in ECs to elicit an anti-AS efect [33]. Indeed, endothelial dysfunction is closely related to the decreased bioavailability of NO due to reduced NO generation in EC or increased inactivation of NO by ROS [34,35].…”

Section: Discussionmentioning

confidence: 99%

Integrating Network Pharmacology and Metabolomics to Explore the Potential Mechanism of Pinolenic Acid against Atherosclerosis

Cao,

Zhang,

Yang

et al. 2024

Journal of Food Biochemistry

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Atherosclerosis (AS) is a global disease that causes a heavy economic burden and can significantly impact human health. Pinolenic acid (PLA) has antioxidant, anti-inflammatory, and lipid-lowering effects. However, it is unclear whether PLA holds a therapeutic promise for AS treatment or prevention. This study aims to investigate whether PLA can effectively treat AS and elucidate its therapeutic mechanism. To this end, potential PLA targets in AS treatment were identified by using network pharmacology. Additionally, an in vitro AS cell model was established by H2O2-induced damaging of human coronary artery endothelial cells (HCAECs). Subsequently, endothelial cell function was evaluated by evaluating cell proliferation, oxidative markers, reactive oxygen species (ROS), and nitric oxide (NO) levels. Cellular metabolomics was further employed to assess differential intracellular metabolites following H2O2 injury. In total, 87 overlapping target genes for PLA and AS were detected. PPI network analysis identified 38 hub genes closely associated with oxidative stress and fatty acid metabolism. Moreover, PLA improved cell survival and reduced oxidative stress injury by activating the NRF2/ARE signaling pathway in vitro. Cellular metabolomics confirmed that PLA might help maintain redox homeostasis and reduce endothelial cell injury by upregulating fatty acid β-oxidation. Taken together, our findings suggest that PLA prevents H2O2-induced HCAEC injury by maintaining redox homeostasis and may, therefore, represent a therapeutic potential for AS.

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“…HFD combined with L-NAME was used to establish the NAFLD mice model, as previously described, representing a compound- and diet-induced NAFLD model [ 42 ]. L-NAME, the NOS inhibitor, can promote hepatic TG and cholesterol by regulating the metabolism of TG synthesis and cholesterol [ 32 , 43 ]. Typical manifestations of NAFLD have been found in mice, including body weight gain, liver weight gain, and improved liver steatosis.…”

Section: Discussionmentioning

confidence: 99%

Exercise-Induced ADAR2 Protects against Nonalcoholic Fatty Liver Disease through miR-34a

et al. 2022

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Nonalcoholic fatty liver disease (NAFLD) is a growing health problem that is closely associated with insulin resistance and hereditary susceptibility. Exercise is a beneficial approach to NAFLD. However, the relief mechanism of exercise training is still unknown. In this study, mice on a normal diet or a high-fat diet (HFD), combined with Nω-nitro-L-arginine methyl ester, hydrochloride (L-NAME) mice, were either kept sedentary or were subjected to a 12-week exercise running scheme. We found that exercise reduced liver steatosis in mice with diet-induced NAFLD. The hepatic adenosine deaminases acting on RNA 2 (ADAR2) were downregulated in NAFLD and were upregulated in the liver after 12-week exercise. Next, overexpression of ADAR2 inhibited and suppression promoted lipogenesis in HepG2 cells treated with oleic acid (OA), respectively. We found that ADAR2 could down-regulate mature miR-34a in hepatocytes. Functional reverse experiments further proved that miR-34a mimicry eliminated the suppression of ADAR2 overexpression in lipogenesis in vitro. Moreover, miR-34a inhibition and mimicry could also affect lipogenesis in hepatocytes. In conclusion, exercise-induced ADAR2 protects against lipogenesis during NAFLD by editing miR-34a. RNA editing mediated by ADAR2 may be a promising therapeutic candidate for NAFLD.

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Suppression of nitric oxide synthase aggravates non-alcoholic steatohepatitis and atherosclerosis in SHRSP5/Dmcr rat via acceleration of abnormal lipid metabolism

Cited by 5 publications

References 53 publications

Oral L-Citrulline Supplementation Improves Fatty Liver and Dyslipidemia in Adolescents with Abdominal Obesity: A Parallel, Double-Blind, Randomized Clinical Trial

Oral L-Citrulline Supplementation Improves Fatty Liver and Dyslipidemia in Adolescents with Abdominal Obesity: A Parallel, Double-Blind, Randomized Clinical Trial

Integrating Network Pharmacology and Metabolomics to Explore the Potential Mechanism of Pinolenic Acid against Atherosclerosis

Exercise-Induced ADAR2 Protects against Nonalcoholic Fatty Liver Disease through miR-34a

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