Lipogenesis in Huh7 cells is promoted by increasing the fructose: Glucose molar ratio

Windemuller, Fernando J.; Xu, Jiele; Rabinowitz, Simon S.; Hussain, M. Mahmood; Schwarz, Steven M.

doi:10.4254/wjh.v8.i20.838

Cited by 6 publications

(4 citation statements)

References 37 publications

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“…In addition, meta-analyses of studies with blood lipid and liver-related end points show no effect in trials that controlled for energy. 35 – 37 Studies in vitro also present conflicting conclusions: some studies showing differential effects of fructose at remarkably low (0.72 mM) concentrations of total monosaccharide with increasing fructose:glucose molar ratios; 38 other studies show no differential effects until higher (25 mM) doses of fructose were used. 39 Such concentrations are generally supra-physiological doses, being significantly higher than concentrations observed in portal blood, which rarely exceed 2 mM.…”

Section: Discussionmentioning

confidence: 99%

Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease

et al. 2018

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Non-alcoholic fatty liver disease (NAFLD) is a serious public health issue associated with high fat, high sugar diets. However, the molecular mechanisms mediating NAFLD pathogenesis are only partially understood. Here we adopt an iterative multi-scale, systems biology approach coupled to in vitro experimentation to investigate the roles of sugar and fat metabolism in NAFLD pathogenesis. The use of fructose as a sweetening agent is controversial; to explore this, we developed a predictive model of human monosaccharide transport, signalling and metabolism. The resulting quantitative model comprising a kinetic model describing monosaccharide transport and insulin signalling integrated with a hepatocyte-specific genome-scale metabolic network (GSMN). Differential kinetics for the utilisation of glucose and fructose were predicted, but the resultant triacylglycerol production was predicted to be similar for monosaccharides; these predictions were verified by in vitro data. The role of physiological adaptation to lipid overload was explored through the comprehensive reconstruction of the peroxisome proliferator activated receptor alpha (PPARα) regulome integrated with a hepatocyte-specific GSMN. The resulting qualitative model reproduced metabolic responses to increased fatty acid levels and mimicked lipid loading in vitro. The model predicted that activation of PPARα by lipids produces a biphasic response, which initially exacerbates steatosis. Our data support the evidence that it is the quantity of sugar rather than the type that is critical in driving the steatotic response. Furthermore, we predict PPARα-mediated adaptations to hepatic lipid overload, shedding light on potential challenges for the use of PPARα agonists to treat NAFLD.

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Section: Discussionmentioning

confidence: 99%

Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease

et al. 2018

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“…With regard to human hepatocyte metabolism and function, these effects have yet to be clearly demonstrated. Using Huh7 cells, Windemuller et al (2016) provided evidence that increasing the molar ratio of fructose to glucose resulted in significant, dose-dependent increases in intracellular TAG; it is unclear if there were concomitant changes in the expression of relevant lipogenic genes as these were not measured. The more global metabolic effect of fructose on cellular metabolism has been explored by culturing HepG2 cells for 48 h in either glucose (5.5 or 10.5 mM) or a combination of glucose (5.5 mM) and fructose (5 mM) and collecting cells at 10 min, 1, 6 and 24 h after 48 h medium replacement (Meissen et al 2015).…”

Section: Summary Of In Vitro Hepatocyte and Adipocyte Cell Culture Stmentioning

confidence: 99%

Challenging metabolic tissues with fructose: tissue‐specific and sex‐specific responses

Pinnick

Hodson

2019

The Journal of Physiology

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Excessive consumption of free sugars (which typically includes a composite of glucose and fructose) is associated with an increased risk of developing chronic metabolic diseases including obesity, non‐alcoholic fatty liver disease (NAFLD), type 2 diabetes and cardiovascular disease. Determining the utilisation, storage and fate of dietary sugars in metabolically relevant tissues is fundamental to understanding their contribution to metabolic disease risk. To date, the study of fructose metabolism has primarily focused on the liver, where it has been implicated in impaired insulin sensitivity, increased fat accumulation and dyslipidaemia. Yet we still have only a limited understanding of the mechanisms by which consumption of fructose, as part of a mixed meal, may alter hepatic fatty acid synthesis and partitioning. Moreover, surprisingly little is known about the metabolism of fructose within other organs, specifically subcutaneous adipose tissue, which is the largest metabolically active organ in the human body and is consistently exposed to nutrient fluxes. This review summarises what is known about fructose metabolism in the liver and adipose tissue and examines evidence for tissue‐specific and sex‐specific responses to fructose.

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“…Conditioned media from HepG2 cells treated with palmitate significantly increased alpha-SMA expression in LX-2 cells, although LX-2 cells directly treated with palmitate did not show the same response, suggesting that a secondary metabolite from palmitate-treated HepG2 cells was responsible for HSC activation [ 20 ]. Windemuller et al [ 26 ] showed that increasing the fructose to glucose ratio in Huh7 cells corresponded with elevated triacylglycerol and cholesterol synthesis, but this effect was not observed with increasing concentrations of glucose. In contrast, HepG2 cells treated with fructose did not show altered expression of lipogenic genes [ 22 ], although a combination of fructose, glucose, and fatty acids (palmitate and oleate) not only increased levels of triacylglycerols, total cholesterol, and inflammatory cytokines, but also upregulated expression of genes involved in carbohydrate and lipid metabolism [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies have investigated changes in intercellular metabolism resulting from exposure to these nutrients in primary or immortalized hepatocytes and hepatic stellate cells (HSCs) [20][21][22][23][24][25][26][27][28]. HSCs are quiescent under physiological conditions, but are activated to a myofibroblastic state in response to injurious stimuli, whereupon they begin to secrete cytokines and components of the extracellular matrix (ECM).…”

Section: Introductionmentioning

confidence: 99%

Palmitate and Fructose Interact to Induce Human Hepatocytes to Produce Pro-Fibrotic Transcriptional Responses in Hepatic Stellate Cells Exposed to Conditioned Media

2020

Cell Physiol Biochem

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BACKGROUND/AIMS: Excessive consumption of dietary fat and sugar is associated with an elevated risk of nonalcoholic fatty liver disease (NAFLD). Hepatocytes exposed to saturated fat or sugar exert effects on nearby hepatic stellate cells (HSCs); however, the mechanisms by which this occurs are poorly understood. We sought to determine whether paracrine effects of hepatocytes exposed to palmitate and fructose produced profibrotic transcriptional responses in HSCs. METHODS: We performed expression profiling of mRNA and lncRNA from HSCs treated with conditioned media (CM) from human hepatocytes treated with palmitate (P), fructose (F), or both (PF). RESULTS: In HSCs exposed to CM from palmitate-treated hepatocytes, we identified 374 mRNAs and 607 lncRNAs showing significant differential expression (log2 foldchange ≥ |1|; FDR ≤0.05) compared to control cells. In HSCs exposed to CM from PF-treated hepatocytes, the number of differentially expressed genes was much higher (1198 mRNAs and 3348 lncRNAs); however, CM from fructose-treated hepatocytes elicited no significant changes in gene expression. Pathway analysis of differentially expressed genes showed enrichment for hepatic fibrosis and hepatic stellate cell activation in P- (FDR =1.30E-04) and PF-(FDR =9.24E-06) groups. We observed 71 lncRNA/nearby mRNA pairs showing differential expression under PF conditions. There were 90 mRNAs and 264 lncRNAs strongly correlated between the PF group and differentially expressed transcripts from a comparison of activated and quiescent HSCs, suggesting that some of the transcriptomic changes occurring in response to PF overlap with HSC activation. CONCLUSION: The results reported here have implications for dietary modifications in the prevention and treatment of NAFLD.

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Lipogenesis in Huh7 cells is promoted by increasing the fructose: Glucose molar ratio

Cited by 6 publications

References 37 publications

Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease

Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease

Challenging metabolic tissues with fructose: tissue‐specific and sex‐specific responses

Palmitate and Fructose Interact to Induce Human Hepatocytes to Produce Pro-Fibrotic Transcriptional Responses in Hepatic Stellate Cells Exposed to Conditioned Media

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