Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease

Lee, Yun Hee; Kim, Sou Hyun; Kim, Sang Nam; Kwon, Hyun Jung; Kim, Jeong Dong; Oh, Ji Youn; Jung, Young Suk

doi:10.18632/oncotarget.10506

Cited by 45 publications

(37 citation statements)

References 50 publications

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“…Previously, a sex-specific activation of Fgf21 expression was observed in humans and animals with various metabolic diseases (Wang et al, 2017;Chukijrungroat et al, 2017;Lee et al, 2016;Gasparin et al, 2018). Our results are in line with data from Gasparin and coauthors (Gasparin et al, 2018), who found that DIO increased Fgf21 mRNA expression in the liver, WAT and BAT in male, but not female mice.…”

Section: Discussionsupporting

confidence: 92%

“…Wang et al (2017) found that higher serum FGF21 levels were associated with an increased risk of type 2 diabetes in Chinese women but not in men. Diets that induce NAFLD also affected hepatic Fgf21 expression in sex-specific manners: highfat high-fructose diet increased Fgf21 expression only in male rats (Chukijrungroat et al, 2017), methioninecholine deficient diet only increased expression in female mice (Lee et al, 2016) and cafeteria obesogenic diet only increased expression in male mice. It is unknown whether the sex differences in the expression of FGF21 are manifested only in metabolic diseases and, possibly, are a consequence of these diseases, or if the activation of Fgf21 expression is sex-specific under natural physiological adaptations to nutritional stresses.…”

Section: Introductionmentioning

confidence: 99%

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Sex Dimorphism in the Fgf21 Gene Expression in Liver and Adipose Tissues is Dependent on the Metabolic Condition

Бажан¹,

Jakovleva²,

Balyibina³

et al. 2019

OnLine Journal of Biological Sciences

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Fibroblast growth factor-21 (FGF21) beneficially affects carbohydrate and lipid metabolism. Previously, a sex-specific activation of Fgf21 expression was observed in humans and animals with metabolic diseases. It is unknown whether the sex differences in the Fgf21 expression are manifested in response to the natural physiological situations of fasting and refeeding. The aim of this work was to determine liver, White Adipose Tissue (WAT) and Brown Adipose Tissue (BAT) expression of genes related to FGF21 signaling in response to 24 h fasting, 6 h refeeding (after 24 h fasting) and Diet-Induced Obesity (DIO) in C57Bl mice of both sexes. Obesity was induced by the consumption of palatable food for 10 weeks. mRNA levels of peroxisome proliferator-activated receptor-a and-γ (Pparα, Pparγ), FGF21 (Fgf21), coactivator of FGF receptors (Klb) and transcriptional coactivator (Pgc-1α) were measured by RT-PCR. The study showed that the fasting-induced increases in hepatic Fgf21 gene expression and circulating FGF21 levels, as well as refeeding-induced increases in local WAT and BAT Fgf21 gene expression, were biased toward females. DIO-induced increase in circulating FGF21 levels, as well as in Fgf21 gene expression in the liver and BAT, were biased toward males. Considering that FGF21 is a novel metabolic regulator of energy homeostasis, sex differences in the responses to anabolic and catabolic stimulus could have translational implications for novel therapeutic outcomes.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Sex Dimorphism in the Fgf21 Gene Expression in Liver and Adipose Tissues is Dependent on the Metabolic Condition

Бажан¹,

Jakovleva²,

Balyibina³

et al. 2019

OnLine Journal of Biological Sciences

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“…43 In fact, the accumulation of hepatic lipids and the consequent development of liver steatosis are twice as common in the postmenopausal period compared to the reproductive age. [44][45][46] In addition, mice fed with a diet deficient in choline and methionine for two weeks show steatosis, an increase in hepatic transaminases, and an increased expression of inflammatory markers with these changes more pronounced in males, 47 corroborating our present findings where EW females did not have alterations in liver morphology or in serum and hepatic CHOL and TG levels.…”

Section: Discussionsupporting

confidence: 87%

Hepatic lipid metabolism in adult rats using early weaning models: sex-related differences

Bertasso

Pietrobon

Silva

et al. 2020

J Dev Orig Health Dis

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Non-pharmacological early weaning (NPEW) induces liver damage in male progeny at adulthood; however, pharmacological early weaning (PEW) does not cause this dysfunction. To elucidate this difference in liver dysfunction between these two models and determine the phenotype of female offspring, de novo lipogenesis, β-oxidation, very low-density lipoprotein (VLDL) export, and gluconeogenesis in both sexes were investigated in the adult Wistar rats that were weaned after a normal period of lactation (control group) or early weaned either by restriction of access to the dams’ teats (NPEW group) or by reduction of dams’ milk production with bromocriptine (PEW group). The offspring received standard diet from weaning to euthanasia (PN180). NPEW males had higher plasma triglycerides and TyG index, liver triglycerides, and cholesterol by de novo lipogenesis, which leads to intracellular lipids accumulation. As expected, hepatic morphology was preserved in PEW males, but they showed increased liver triglycerides. The only molecular difference between PEW and NPEW males was in acetyl-CoA carboxylase-1 (ACC-1) and stearoyl-CoA desaturase-1 (SCD-1), which were lower in PEW animals. Both early weaning (EW) females had no changes in liver cholesterol and triglyceride contents, and the hepatic cytoarchitecture was preserved. The expression of microsomal triglyceride transfer protein was increased in both the female EW groups, which could constitute a protective factor. The changes in hepatic lipid metabolism in EW offspring were less marked in females. EW impacted in the hepatic cytoarchitecture only in NPEW males, which showed higher ACC-1 and SCD-1 when compared to the PEW group. As these enzymes are lipogenic, it could explain a worsened liver function in NPEW males.

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“…Additionally, the Hif-p4h-2 gt/gt mice on the HF-MCD diet had less WAT, and interestingly, they showed improved browning of WAT, which was associated with increased heat production. This likely contributed to less hepatic steatosis in the Hif-p4h-2 gt/gt mice, as WAT browning protecting against NAFLD has been reported on an MCD diet [28,29]. However, this is the first report associating HIF-P4H inhibition with induced browning of WAT and increased thermogenesis, while earlier reports associate environmental hypoxia with HIF pathway activation and WAT browning [43,44].…”

Section: Discussionmentioning

confidence: 65%

“…Browning of WAT has been shown to be a protective mechanism against NAFLD in mice on MCD diet [28,29]. Therefore, we next studied the expression of uncoupling protein 1 (UCP1) in the WAT of the HF-MCD diet-fed mice.…”

Section: Increased Heat Production In the Hif-p4h-2-deficient Mice Onmentioning

confidence: 99%

HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) parallels the global obesity epidemic with unmet therapeutic needs. We investigated whether inhibition of hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2), a key cellular oxygen sensor whose inhibition stabilizes HIF, would protect from NAFLD by subjecting HIF-P4H-2-deficient (Hif-p4h-2 gt/gt ) mice to a high-fat, highfructose (HFHF) or high-fat, methionine-choline-deficient (HF-MCD) diet. On both diets, the Hif-p4h-2 gt/gt mice gained less weight and had less white adipose tissue (WAT) and its inflammation, lower serum cholesterol levels, and lighter livers with less steatosis and lower serum ALT levels than the wild type (WT). The intake of fructose in majority of the Hif-p4h-2 gt/gt tissues, including the liver, was 15-35% less than in the WT. We found upregulation of the key fructose transporter and metabolizing enzyme mRNAs, Slc2a2, Khka, and Khkc, and higher ketohexokinase activity in the Hif-p4h-2 gt/gt small intestine relative to the WT, suggesting enhanced metabolism of fructose in the former. On the HF-MCD diet, the Hif-p4h-2 gt/gt mice showed more browning of the WAT and increased thermogenesis. A pharmacological pan-HIF-P4H inhibitor protected WT mice on both diets against obesity, metabolic dysfunction, and liver damage. These data suggest that HIF-P4H-2 inhibition could be studied as a novel, comprehensive treatment strategy for NAFLD. Key messages• HIF-P4H-2 inhibition enhances intestinal fructose metabolism protecting the liver.• HIF-P4H-2 inhibition downregulates hepatic lipogenesis.• Induced browning of WAT and increased thermogenesis can also mediate protection.• HIF-P4H-2 inhibition offers a novel, comprehensive treatment strategy for NAFLD.

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Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease

Cited by 45 publications

References 50 publications

Sex Dimorphism in the Fgf21 Gene Expression in Liver and Adipose Tissues is Dependent on the Metabolic Condition

Sex Dimorphism in the Fgf21 Gene Expression in Liver and Adipose Tissues is Dependent on the Metabolic Condition

Hepatic lipid metabolism in adult rats using early weaning models: sex-related differences

HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD

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