Regulation of hepatic gene expression by saturated fatty acids

Vallim, T.; Salter, Andrew M.

doi:10.1016/j.plefa.2010.02.016

Cited by 72 publications

(59 citation statements)

References 75 publications

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“…The present study showed that a single dose of PO differentially regulated the canonical pathways TWEAK and AHR. The AHR pathway promotes NAFLD via upregulation of fatty acid transport (42), which is in line with the observed upregulation of Fabp5 and increase in HCL content in humans. The TNF-related TWEAK is known to promote cell turnover homeostasis through the NF-κB and p38 MAPK pathways and could serve as a biomarker of obesity and T2DM (43).…”

Section: Figure 2 Time Courses Of Circulating Metabolites and Hormonsupporting

confidence: 83%

“…The marked alterations in hepatic glucose fluxes in humans and the predominant hepatic insulin resistance in mice raise interest in the effects of saturated fatty acids on hepatic gene expression, which has been previously examined mostly upon exposure to polyunsaturated fatty acids (42). The present study showed that a single dose of PO differentially regulated the canonical pathways TWEAK and AHR.…”

Section: Figure 2 Time Courses Of Circulating Metabolites and Hormonsupporting

confidence: 47%

See 1 more Smart Citation

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Hernández¹,

Kahl²,

Seelig³

et al. 2017

Journal of Clinical Investigation

148

130

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H and ex vivo2 H magnetic resonance spectroscopy before and during hyperinsulinemiceuglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses.RESULTS. PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-κB, and TNF-related weak inducer of apoptosis (TWEAK). CONCLUSION.Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD. PO results in increased circulating TG, glucagon, and incretins. After PO administration, TG in plasma rose by 59% (area under the time curve [AUC], P < 0.001) and by 156% in chylomicrons (AUC, P = 0.009) (Figure 2A). The AUC for plasma free fatty acids (FFA) ( Figure 2B) and insulin concentrations ( Figure 2C) was unchanged, while the AUC for plasma C-peptide was 28% higher after PO ingestion versus VCL (P < 0.005, Figure 2D). Of note, FFA were increased at 300, 420, and 480 minutes. Blood glucose levels were not different between PO-and VCL-treated groups ( Figure 2E). Plasma glucagon rose by 41% (AUC, P < 0.0001) only after PO ingestion ( Figure 2F). Also, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels were markedly increased and remained elevated after PO ingestion (both P < 0.005) (Supplemental Figure 2; supplemental material available online with this article; https://doi.org/10.1172/ JCI89444DS1). Circulating levels of TNF-α, IL-6, fetuin-A, chemerin, omentin, and cortisol were not different between PO and VCL groups (P > 0.5 for all) (Supplemental Table 1). REGISTRATION. The Journal of Clinical Investigation C L I N I C A L M E D I C I N EPO induces insulin resistance at whole-body, liver, and adipose tissue levels. Insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp tests in healthy humans. Steady state was reached (Supplemental Figure 1), and pertinent parameters were analyzed during this time. PO ingestion reduced WBIS by 25% compared with VCL treatment (P = 0.0005, Figure 3A). Furthermore, after PO, volunteers also showed a decrease of 22% (P = 0.002) in the rate of glucose disappearance (Rd), mostly due to a 33% (P = 0.01) reduction in glucose oxidation (GOX), while the rate of nonoxidative glucose disposal remained unchanged

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Section: Figure 2 Time Courses Of Circulating Metabolites and Hormonsupporting

confidence: 83%

Section: Figure 2 Time Courses Of Circulating Metabolites and Hormonsupporting

confidence: 47%

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Hernández¹,

Kahl²,

Seelig³

et al. 2017

Journal of Clinical Investigation

148

130

View full text Add to dashboard Cite

show abstract

“…been evaluated as a potential new treatment of NAFLD (Ahmed and Byrne, 2007;Vallim and Salter, 2010). LXRs are members of the nuclear receptor superfamily of ligand-activated transcriptional factors involved in the regulation of lipid metabolism and inflammatory process (Torocsik et al, 2009).…”

Section: Hc3s Decreases Serum and Hepatic Lipidsmentioning

confidence: 99%

5-Cholesten-3β,25-Diol 3-Sulfate Decreases Lipid Accumulation in Diet-Induced Nonalcoholic Fatty Liver Disease Mouse Model

Kim

Bai

et al. 2012

Mol Pharmacol

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Sterol regulatory element-binding protein-1c (SREBP-1c) increases lipogenesis at the transcriptional level, and its expression is upregulated by liver X receptor a (LXRa). The LXRa/ SREBP-1c signaling may play a crucial role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We previously reported that a cholesterol metabolite, 5-cholesten-3b,25-diol 3-sulfate (25HC3S), inhibits the LXRa signaling and reduces lipogenesis by decreasing SREBP-1c expression in primary hepatocytes. The present study aims to investigate the effects of 25HC3S on lipid homeostasis in diet-induced NAFLD mouse models. NAFLD was induced by feeding a high-fat diet (HFD) in C57BL/6J mice. The effects of 25HC3S on lipid homeostasis, inflammatory responses, and insulin sensitivity were evaluated after acute treatments or long-term treatments. Acute treatments with 25HC3S decreased serum lipid levels, and long-term treatments decreased hepatic lipid accumulation in the NAFLD mice. Gene expression analysis showed that 25HC3S significantly suppressed the SREBP-1c signaling pathway that was associated with the suppression of the key enzymes involved in lipogenesis: fatty acid synthase, acetyl-CoA carboxylase 1, and glycerol-3-phosphate acyltransferase. In addition, 25HC3S significantly reduced HFD-induced hepatic inflammation as evidenced by decreasing tumor necrosis factor and interleukin 1 a/b mRNA levels. A glucose tolerance test and insulin tolerance test showed that 25HC3S administration improved HFD-induced insulin resistance. The present results indicate that 25HC3S as a potent endogenous regulator decreases lipogenesis, and oxysterol sulfation can be a key protective regulatory pathway against lipid accumulation and lipid-induced inflammation in vivo.

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“…Beside the direct immediate effect on ROS production, mostly via the function of mitochondrial ETC, fatty acids and carbohydrates may have long-term indirect effects via regulation of expression of either ROS-generating or antioxidant enzymes. There are at least three transcription factor families, peroxisome proliferator-activated receptors (PPAR), liver X receptors, and sterol response elementbinding proteins, which play a major role in the fatty acidinduced regulation of gene transcription (360). The classic example of a transcription factor, which can be directly activated by fatty acids, is PPAR (360).…”

mentioning

confidence: 99%

Nutritional Countermeasures Targeting Reactive Oxygen Species in Cancer: From Mechanisms to Biomarkers and Clinical Evidence

Samoylenko

Hossain²,

Mennerich³

et al. 2013

Antioxidants & Redox Signaling

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Reactive oxygen species (ROS) exert various biological effects and contribute to signaling events during physiological and pathological processes. Enhanced levels of ROS are highly associated with different tumors, a Western lifestyle, and a nutritional regime. The supplementation of food with traditional antioxidants was shown to be protective against cancer in a number of studies both in vitro and in vivo. However, recent largescale human trials in well-nourished populations did not confirm the beneficial role of antioxidants in cancer, whereas there is a well-established connection between longevity of several human populations and increased amount of antioxidants in their diets. Although our knowledge about ROS generators, ROS scavengers, and ROS signaling has improved, the knowledge about the direct link between nutrition, ROS levels, and cancer is limited. These limitations are partly due to lack of standardized reliable ROS measurement methods, easily usable biomarkers, knowledge of ROS action in cellular compartments, and individual genetic predispositions. The current review summarizes ROS formation due to nutrition with respect to macronutrients and antioxidant micronutrients in the context of cancer and discusses signaling mechanisms, used biomarkers, and its limitations along with large-scale human trials.

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Regulation of hepatic gene expression by saturated fatty acids

Cited by 72 publications

References 75 publications

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

5-Cholesten-3β,25-Diol 3-Sulfate Decreases Lipid Accumulation in Diet-Induced Nonalcoholic Fatty Liver Disease Mouse Model

Nutritional Countermeasures Targeting Reactive Oxygen Species in Cancer: From Mechanisms to Biomarkers and Clinical Evidence

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