Involvement of SIRT1–AMPK signaling in the protective action of indole-3-carbinol against hepatic steatosis in mice fed a high-fat diet

Choi, Youngshim; Yanagawa, Yasuko; Kim, Soyoung; Park, Tae Sun

doi:10.1016/j.jnutbio.2012.11.007

Cited by 33 publications

(18 citation statements)

References 40 publications

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“…These responses were closely associated with SIRT1 deacetylase activity, showing that the lipid-related proteins were controlled by a SIRT1-dependent pathway (Supplemental Figs 2A, 5D and 6D). Our results were consistent with previous reports, which showed that activation of SIRT1 by pharmacological treatment has lipid-lowering effects through AMPK signalling8930. Additionally, it is well known that AMPK phosphorylates and regulates several hepatic metabolic enzymes, such as ACC and FAS, which in turn increases fatty acid oxidation31.…”

Section: Discussionsupporting

confidence: 93%

Lycium barbarum polysaccharide attenuates high-fat diet-induced hepatic steatosis by up-regulating SIRT1 expression and deacetylase activity

et al. 2016

Sci Rep

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In this study, we aimed to investigate the protective effects and underlying mechanism of Lycium barbarum polysaccharide (LBP) on high-fat-induced nonalcoholic fatty liver disease (NAFLD). Recently, sirtuin 1 (SIRT1) has been shown to play an important role in the regulation of hepatocellular lipid metabolism. Here, we demonstrated that LBP up-regulates SIRT1 deacetylase activity and protein expression by enhancing the NAD+/NADH ratio. Subsequently, LBP promoted LKB1 deacetylation and AMPK phosphorylation via SIRT1-dependent signalling. We also found that LBP increases acetyl-CoA carboxylase (ACC) phosphorylation and adipose triglyceride lipase (ATGL) protein expression and decreases fatty acid synthase (FAS) by activating the SIRT1/LKB1/AMPK pathway in vitro and in vivo. However, SIRT1 small interfering RNA (siRNA)-mediated knockdown reversed the LBP-mediated effects on ACC, FAS and ATGL. Moreover, LBP elevated carnitine palmitoyltransferase-1 alpha (CPT-1α) expression by suppressing malonyl-CoA accumulation. Taken together, our data indicate that LBP plays a vital role in the regulation of hepatic lipid metabolism and that pharmacological activation of SIRT1 by LBP may be a strategy for the prevention of NAFLD.

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Section: Discussionsupporting

confidence: 93%

Lycium barbarum polysaccharide attenuates high-fat diet-induced hepatic steatosis by up-regulating SIRT1 expression and deacetylase activity

et al. 2016

Sci Rep

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“…(30) While much evidence increasingly verifies the association between gut microbiota and NAFLD/NASH pathogenesis, it was the study by Park et al that validated a role for indole-3-carbinol, a derivate of indole, in the amelioration of HFD-induced NAFLD phenotype in mice. (31) A complementary study also indicated that the levels of I3A were decreased in livers of HFD-fed mice compared with control, (26) suggesting a role for I3A in NAFLD phenotype. These findings led us to postulate a role for indole in NAFLD pathophysiology.…”

Section: Discussionmentioning

confidence: 95%

Indole Alleviates Diet‐Induced Hepatic Steatosis and Inflammation in a Manner Involving Myeloid Cell 6‐Phosphofructo‐2‐Kinase/Fructose‐2,6‐Biphosphatase 3

et al. 2020

Hepatology

102

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BaCKgRoUND aND aIMS: Indole is a microbiota metabolite that exerts anti-inflammatory responses. However, the relevance of indole to human non-alcoholic fatty liver disease (NAFLD) is not clear. It also remains largely unknown whether and how indole acts to protect against NAFLD. The present study sought to examine the association between the circulating levels of indole and liver fat content in human subjects and explore the mechanisms underlying indole actions in mice with diet-induced NAFLD. appRoaCH aND ReSUltS: In a cohort of 137 subjects, the circulating levels of indole were reversely correlated with body mass index. In addition, the circulating levels of indole in obese subjects were significantly lower than those in lean subjects and were accompanied with increased liver fat content. At the whole-animal level, treatment of high-fat diet (HFD)-fed C57BL/6J mice with indole caused significant decreases in the severity of hepatic steatosis and inflammation. In cultured cells, indole treatment stimulated the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a master regulatory gene of glycolysis, and suppressed macrophage proinflammatory activation in a PFKFB3-dependent manner. Moreover, myeloid cell-specific PFKFB3 disruption exacerbated the severity of HFD-induced hepatic steatosis and inflammation and blunted the effect of indole on alleviating diet-induced NAFLD phenotype. CoNClUSIoNS: Taken together, our results demonstrate that indole is relevant to human NAFLD and capable of alleviating diet-induced NAFLD phenotypes in mice in a myeloid cell PFKFB3-dependent manner. Therefore, indole mimetic and/or macrophage-specific PFKFB3 activation may be the viable preventive and/or therapeutic approaches for inflammation-associated diseases including NAFLD. (Hepatology 2020;72:1191-1203). N onalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and progresses to nonalcoholic steatohepatitis (NASH) when the liver displays overt inflammatory damage. (1,2) As the advanced form of NAFLD, NASH is one of the most common causes of liver

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“…SIRT1 and phosphorylated (active) AMPK (p-AMPK) are key regulators of both lipogenesis and fatty acid oxidation in the liver [37, 38]. Expression of SIRT1 and phosphorylation of AMPK were significantly decreased in the livers of HFD-fed mice compared with control mice and walnuts supplementation completely prevented the alteration of the levels of these two proteins (Figs.…”

Section: Resultsmentioning

confidence: 99%

Preventive effects of dietary walnuts on high-fat-induced hepatic fat accumulation, oxidative stress and apoptosis in mice

Choi

Abdelmegeed

Song

2016

The Journal of Nutritional Biochemistry

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We hypothesized that dietary walnut would prevent high-fat-diet (HFD)-induced hepatic apoptosis based on its antioxidant properties. Male C57BL/6J mice were fed a rodent chow or HFD (45% energy-derived) ± walnuts (21.5% energy-derived) for 6 weeks. Liver histological and biochemical analyses revealed significantly elevated fat accumulation in mice fed HFD compared to mice fed the chow or HFD+walnuts. Walnut supplementation prevented HFD-mediated alteration of the levels of key proteins in lipid homeostasis such as Sirt1, AMPK and FAS, leading to decreased fat accumulation. In addition, walnut supplementation to HFD significantly decreased the hepatic levels of cytochrome P450-2E1, nitrated proteins and lipid peroxidation. Furthermore, walnut supplementation decreased the activated cell death-associated p-JNK and p-p38K accompanied with increased hepatocyte apoptosis in HFD group. The beneficial effects of dietary walnut likely result, at least partially, from its antioxidant ingredients and attenuating HFD-induced hepatic steatosis, nitroxidative stress and apoptosis.

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Involvement of SIRT1–AMPK signaling in the protective action of indole-3-carbinol against hepatic steatosis in mice fed a high-fat diet

Cited by 33 publications

References 40 publications

Lycium barbarum polysaccharide attenuates high-fat diet-induced hepatic steatosis by up-regulating SIRT1 expression and deacetylase activity

Lycium barbarum polysaccharide attenuates high-fat diet-induced hepatic steatosis by up-regulating SIRT1 expression and deacetylase activity

Indole Alleviates Diet‐Induced Hepatic Steatosis and Inflammation in a Manner Involving Myeloid Cell 6‐Phosphofructo‐2‐Kinase/Fructose‐2,6‐Biphosphatase 3

Preventive effects of dietary walnuts on high-fat-induced hepatic fat accumulation, oxidative stress and apoptosis in mice

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