Characteristics of hepatic insulin‐sensitive nonalcoholic fatty liver disease

Shigiyama, Fumika; Kumashiro, Naoki; Furukawa, Yasushi; Fukushima, Takashi; Takeno, Kageumi; Wakui, Noritaka; Ikehara, Takashi; Nagai, Hidenari; Taka, Hikari; Fujimura, Tsutomu; Uchino, Hiroshi; Tamura, Yasuaki; Watada, Hirotaka; Nemoto, Tetsuo; Shiraga, Nobuyuki; Sumino, Yasukiyo; Hirose, Takahisa

doi:10.1002/hep4.1077

Cited by 17 publications

(20 citation statements)

References 59 publications

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“…Citrate was also positively correlated with glucose (r = 0.2839, p < 0.05) and HbA1c (r = 0.3844, p < 0.001). This is similar to a previous report by Shigiyama et al that showed citrate levels are elevated in NAFLD patients with a high hepatic insulin sensitivity group [41]. The same study also reported an increase in succinate and aconitate, but we did not find a statistically significant association of these metabolites with glucose in our subjects.…”

Section: Discussionsupporting

confidence: 92%

Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

Sandlers

Shah

Pearce

et al. 2020

JCM

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Nonalcoholic liver disease (NAFLD) is manifested with a wide spectrum of clinical symptoms and is closely associated with the metabolic syndrome, inflammation, and mitochondrial dysfunction. Although the mechanism of mitochondrial dysfunction in NAFLD is still not fully elucidated, multiple studies have demonstrated evidence of molecular, biochemical, and biophysical mitochondrial abnormalities in NAFLD. Given the association between NAFLD and mitochondrial dysfunction, the aim of this study is to analyze circulating levels of Krebs cycle intermediates in a cohort of NAFLD-affected individuals and matching healthy controls and to correlate our findings with the liver function metrics. Standard serum biochemistry and Krebs cycle intermediates were analyzed in NAFLD (n = 22) and matched control (n = 67) cohorts. Circulating levels of isocitrate and citrate were significantly (p < 0.05) elevated in the NAFLD cohort of patients. The area under the curve (AUROC) for these two metabolites exhibited a moderate clinical utility. Correlations between plasma Krebs cycle intermediates and standard clinical plasma metrics were explored by Pearson’s correlation coefficient. The data obtained for plasma Krebs cycle intermediates suggest pathophysiological insights that link mitochondrial dysfunction with NAFLD. Our findings reveal that plasma isocitrate and citrate can discriminate between normal and NAFLD cohorts and can be utilized as noninvasive markers of mitochondrial dysfunction in NAFLD. Future studies with large populations at different NAFLD stages are warranted.

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Section: Discussionsupporting

confidence: 92%

Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

Sandlers

Shah

Pearce

et al. 2020

JCM

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“…Altered mitochondrial parameters are thought to be linked to insulin resistance (45,63). Our group has also reported that mitochondrial dysfunction is associated with hepatic insulin resistance in nonalcoholic fatty liver disease in humans (55). In addition, increased acylcarnitine levels may play a causal role in the development of insulin resistance through their proinflammatory effects (49).…”

Section: Discussionmentioning

confidence: 92%

“…First, hepatic steatosis was evaluated in this study by increased hepatic triglycerides content. Because sometimes hepatic triglycerides become inert storage and hepatic insulin-sensitive fatty liver exists in humans (55), future studies should assess other lipid species, such as diacylglycerol and ceramide, which have been implicated in mediating insulin resistance (27,52). Second, no causality can be ascertained due to the lack of gain or loss of function analysis.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of sleep deprivation-induced hepatic steatosis and insulin resistance in mice

Shigiyama

Kumashiro

Tsuneoka

et al. 2018

American Journal of Physiology-Endocrinology and Metabolism

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Sleep deprivation is associated with increased risk for type 2 diabetes mellitus. However, the underlying mechanisms of sleep deprivation-induced glucose intolerance remain elusive. The aim of this study was to investigate the mechanisms of sleep deprivation-induced glucose intolerance in mice with a special focus on the liver. We established a mouse model of sleep deprivation-induced glucose intolerance using C57BL/6J male mice. A single 6-hr sleep deprivation by the gentle handling method under fasting condition induced glucose intolerance. Hepatic glucose production assessed by pyruvate challenge test was significantly increased, as was hepatic triglyceride content (by 67.9%) in the sleep deprivation group, compared with freely sleeping control mice. Metabolome and microarray analyses were used to evaluate hepatic metabolites and gene expression levels and determine the molecular mechanisms of sleep deprivation-induced hepatic steatosis. Hepatic metabolites, such as acetyl CoA, 3β-hydroxybutyric acid, and certain acylcarnitines were significantly increased in the sleep deprivation group, suggesting increased lipid oxidation in the liver. In contrast, fasted sleep-deprived mice showed that hepatic gene expression levels of Elovl3, Lpin1, Plin4, Plin5 and Acot1, which are known to play lipogenic roles, were 2.7, 4.5, 3.7, 2.9, and 2.8 times, respectively, those of the fasted sleeping control group, as assessed by quantitative RT-PCR. Sleep deprivation-induced hepatic steatosis and hepatic insulin resistance seem to be mediated through upregulation of hepatic lipogenic enzymes.

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“…Energy intake was assessed using the validated Brief self‐administered Diet‐History Questionnaire (BDHQ) …”

Section: Methodsmentioning

confidence: 99%