Long-term exposure to high-sucrose diet down-regulates hepatic endoplasmic reticulum-stress adaptive pathways and potentiates de novo lipogenesis in weaned male mice

Flister, Karla Frida Torres; Pinto, Bruno; França, Lucas Martins; Coêlho, Caio Fernando Ferreira; Santos, Pâmela Costa dos; Vale, Caroline Castro; Kajihara, Daniela; Debbas, Victor; Laurindo, Francisco Rafael Martins

doi:10.1016/j.jnutbio.2018.09.007

Cited by 28 publications

(13 citation statements)

References 73 publications

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“…Since then, it has been reliably validated in comparison to other methods, such as euglycaemic clamp and HOMA-IR, [53][54][55][56] and consistently applied for studies in both rats [57][58][59][60] and mice. 13,[61][62][63] Next, we sought to characterise the transcriptional profile of DNL-related genes to assess the impact of both increased portal FFA levels and hepatocyte sucrose-derived fructose uptake per se on lipid metabolism in the liver. At day 60, HSD mice showed threefold increased SCD-1 transcriptional levels, which coincided with increased gene expression of PPAR-α.…”

Section: Discussionmentioning

confidence: 99%

“…We have recently described this sole upregulation of SCD-1 gene expression in chronically HSD-fed mice. 13 SCD-1 has been shown to mediate the induction of SREBP-1c expression by chronic fructose feeding, which partially activates a positive feedback loop to further induce the expression of SCD-1 gene and promote TAG synthesis. 12,67 However, absence of FASN and DGAT-2 induction suggests a minor role for the fructose -SCD-1 -SREBP-1c axis activation, favouring the FFA-driven SCD-1 overexpression in a SREBP-1c-independent pathway.…”

Section: Discussionmentioning

confidence: 99%

“…12 In a previous report, we showed that exposure of weaned mice to an isocaloric high-sucrose diet (HSD) for 90 days increased transcriptional levels of both ChREBP and SREBP1 in a time-dependent manner with consequent NAFLD onset, but no progression into NASH. 13 The close relationship between obesity and NAFLD has been ascribed to the direct involvement of white adipose tissue (WAT), which releases a variety of bioactive substances, such as free fatty acids (FFA), leptin, adiponectin and inflammatory cytokines. Ultimately, these adipokines exert important paracrine and endocrine functions on energy balance and metabolic homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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Post-weaning exposure to high-sucrose diet induces early non-alcoholic fatty liver disease onset and progression in male mice: role of dysfunctional white adipose tissue

França

Santos

Barroso

et al. 2020

J Dev Orig Health Dis

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Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) particularly among chronic consumers of added sugar-rich diets. However, the impact of early consumption of such diets on NAFLD onset and progression is unclear. Thus, this study sought to characterise metabolic factors involved in NAFLD progression in young mice fed with a high-sucrose diet (HSD). Male Swiss mice were fed HSD or regular chow (CTR) from weaning for up to 60 or 90 days. Obesity development, glucose homeostasis and serum biochemical parameters were determined at each time-point. At day 90, mice were euthanised and white adipose tissue (WAT) collected for lipolytic function assessment and liver for histology, gene expression and cytokines quantification. At day 60, HSD mice presented increased body mass, hypertriglyceridemia, peripheral insulin resistance (IR) and simple steatosis. Upon 90 days on diet, WAT from HSD mice displayed impaired insulin sensitivity, which coincided with increased fasting levels of glucose and free fatty acids (FFA), as well as NAFLD progression to NASH. Transcriptional levels of lipogenic genes, particularly stearoyl-CoA desaturase-1, were consistently increased, leading to hepatic leukocyte infiltration and pro-inflammatory cytokines spillover. Therefore, our dataset supports IR triggering in the WAT as a major factor for dysfunctional release of FFA towards portal circulation and consequent upregulation of lipogenic genes and hepatic inflammatory onset, which decisively concurred for NAFLD-to-NASH progression in young HSD-fed mice. Notwithstanding, this study forewarns against the early introduction of dietary sugars in infant diet, particularly following breastfeeding cessation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Post-weaning exposure to high-sucrose diet induces early non-alcoholic fatty liver disease onset and progression in male mice: role of dysfunctional white adipose tissue

França

Santos

Barroso

et al. 2020

J Dev Orig Health Dis

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“…In fact, DNL is mainly regulated by ER membrane-localized transcription factors, Srebp-1c for FA synthesis and Srebp-2 for cholesterol synthesis [30]. A great deal of evidence has shown that chronic ER stress upregulated Srebps directly or indirectly, promoting TG and cholesterol synthesis and storage, which contributed to hepatic steatosis development [31,32]. A previous study showed that ALA downregulated TG and cholesterol biosynthesis pathway by suppressing Srebp-1c and Srebp-2 protein expression [33].…”

Section: Discussionmentioning

confidence: 99%

Plant Sterol Ester of α-Linolenic Acid Attenuates Nonalcoholic Fatty Liver Disease by Rescuing the Adaption to Endoplasmic Reticulum Stress and Enhancing Mitochondrial Biogenesis

Han

Guo

et al. 2019

Oxidative Medicine and Cellular Longevity

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Nonalcoholic fatty liver disease (NAFLD) is becoming more common in the world and is presenting a great challenge concerning prevention and treatment. Plant sterol ester of α-linolenic acid (PS-ALA) has a potential benefit to NAFLD. To examine the effect of PS-ALA on NAFLD, C57BL/6J mice were given a control diet, high fat and high cholesterol diet (HFD), and HFD plus 2% PS, 1.3% ALA, or 3.3% PS-ALA for 16 weeks. Our results showed that PS-ALA treatment suppressed hepatic steatosis, ameliorated lipid disorder, attenuated inflammatory response, and inhibited oxidative stress. In the molecular level, PS-ALA downregulated high transcriptional and translational levels of endoplasmic reticulum (ER) stress markers (Grp78 and Chop) leading to decreased protein expression of transcription factor and key enzymes involved in de novo lipogenesis (Srebp-1c and Fas) and cholesterol synthesis (Srebp-2 and Hmgcr). In parallel, PS-ALA blocked Nlrp3 activation and reduced release of IL-1β and IL-18 via inhibiting ER stress-induced sensitization of unfolded protein response sensors (Ire1α and Xbp1s). Finally, PS-ALA improved HFD-induced mitochondrial damage and fatty acid accumulation as exhibited by higher protein and mRNA expression of key genes administering mitochondrial biogenesis (Pgc-1α, Nrf1, and Tfam) and fatty acid β-oxidation (Pparα and Cpt1a). In conclusion, our study originally demonstrated that PS-ALA rescued ER stress, enhanced mitochondrial biogenesis, and thus ameliorated NAFLD.

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“…Bitter melon HFS supplementation also restored Scd1 mRNA expression to LFD-fed levels. The pattern of hepatic Scd1 mRNA is particularly noteworthy, in that, studies of diet-induced obesity and metabolic dysfunction in male mice typically show increased expression of this lipogenic gene in response to high-fat or high-sucrose feeding [41,42]. Like upregulation of Cd36 mRNA, botanical-mediated increased Scd1 mRNA levels in the liver of the female mice may represent compensatory upregulation.…”

Section: Effects Of Hfs Diet On Markers Of Fatty Acid Oxidation and Imentioning

confidence: 99%

Adaptive Fat Oxidation Is Coupled with Increased Lipid Storage in Adipose Tissue of Female Mice Fed High Dietary Fat and Sucrose

Fuller

Mendoza

et al. 2020

Nutrients

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Western diets high in fat and sucrose are associated with metabolic syndrome (MetS). Although the prevalence of MetS in women is comparable to that in men, metabolic adaptations in females to Western diet have not been reported in preclinical studies. This study investigates the effects of Western diet on risk factors for MetS in female mice. Based on our earlier studies in male mice, we hypothesized that dietary supplementation with extracts of Artemisia dracunculus L. (PMI5011) and Momordica charantia (bitter melon) could affect MetS risk factors in females. Eight-week-old female mice were fed a 10% kcal fat, 17% kcal sucrose diet (LFD); high-fat, high-sucrose diet (HFS; 45% kcal fat, 30% kcal sucrose); or HFS diet with PMI5011 or bitter melon for three months. Body weight and adiposity in all HFS groups were greater than the LFD. Total cholesterol level was elevated with the HFS diets along with LDL cholesterol, but triglycerides and free fatty acids were unchanged from the LFD. Over the three month period, female mice responded to the HFS diet by adaptive increases in fat oxidation energy in muscle and liver. This was coupled with increased fat storage in white and brown adipose tissue depots. These responses were enhanced with botanical supplementation and confer protection from ectopic lipid accumulation associated with MetS in female mice fed an HFS diet.

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Long-term exposure to high-sucrose diet down-regulates hepatic endoplasmic reticulum-stress adaptive pathways and potentiates de novo lipogenesis in weaned male mice

Cited by 28 publications

References 73 publications

Post-weaning exposure to high-sucrose diet induces early non-alcoholic fatty liver disease onset and progression in male mice: role of dysfunctional white adipose tissue

Post-weaning exposure to high-sucrose diet induces early non-alcoholic fatty liver disease onset and progression in male mice: role of dysfunctional white adipose tissue

Plant Sterol Ester of α-Linolenic Acid Attenuates Nonalcoholic Fatty Liver Disease by Rescuing the Adaption to Endoplasmic Reticulum Stress and Enhancing Mitochondrial Biogenesis

Adaptive Fat Oxidation Is Coupled with Increased Lipid Storage in Adipose Tissue of Female Mice Fed High Dietary Fat and Sucrose

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