Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars - PubMed (original) (raw)

Clinical Trial

. 2018 Aug;41(8):1732-1739.

doi: 10.2337/dc18-0071. Epub 2018 May 29.

Sanja Sädevirta 1 2, You Zhou 1 3, Brandon Kayser 4, Ashfaq Ali 5, Linda Ahonen 5, Susanna Lallukka 1 2, Véronique Pelloux 4, Melania Gaggini 6, Ching Jian 7, Antti Hakkarainen 8, Nina Lundbom 8, Helena Gylling 2, Anne Salonen 7, Matej Orešič 5 9 10, Tuulia Hyötyläinen 5 11, Marju Orho-Melander 12, Aila Rissanen 13, Amalia Gastaldelli 6, Karine Clément 4 14, Leanne Hodson 15, Hannele Yki-Järvinen 16 2

Affiliations

Clinical Trial

Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars

Panu K Luukkonen et al. Diabetes Care. 2018 Aug.

Abstract

Objective: Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG.

Research design and methods: We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks.

Results: Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression.

Conclusions: Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.

Trial registration: ClinicalTrials.gov NCT02133144.

© 2018 by the American Diabetes Association.

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Figures

Figure 1

Figure 1

Design of the study (A), overfeeding-induced changes in FA composition of VLDL-TG in the groups (B), IHTG before (B) and after (A) overfeeding (C), and changes in IHTG between the groups (D). The subjects were randomized into overfeeding saturated fat (SAT), unsaturated fat (UNSAT), or simple sugars (CARB) groups. All subjects underwent metabolic studies at baseline and after 3 weeks of overfeeding. At these visits, IHTG content was determined by 1H-MRS, hepatic DNL from 2H2O enrichment in VLDL-TG palmitate, adipose tissue lipolysis by [2H5]glycerol in the basal state and during euglycemic hyperinsulinemia, plasma ceramides by ultra high-performance liquid chromatography–mass spectrometry, and endotoxemia by fecal 16S rRNA and serum LBP-to-sCD14 ratio. In addition, adipose tissue transcriptome was determined by microarray. B: The _x_-axis shows the change in percentage FA in VLDL-TG after vs. before overfeeding, and the y_-axis shows the specific FAs in VLDL-TG. Data are shown as mean ± SEM. *P < 0.05,**P < 0.01, and ***P < 0.001 within groups; †_P < 0.05 between groups.

Figure 2

Figure 2

Overfeeding-induced changes in hepatic de novo lipogenesis (A), basal glycerol _R_a (B), and glycerol R_a (C) during euglycemic hyperinsulinemia. The y_-axes indicate the change of mean values after vs. before overfeeding within groups. Data are shown as medians (interquartile ranges) in panel A and as mean ± SEM in B and C. *P < 0.05 within group; †_P < 0.05 and ††_P < 0.01 between groups. D: Adipose tissue transcriptome. The bubble grid shows the reporter test statistics (proportional to size and color intensity) of relative gene expression after compared with before overfeeding. Only pathways significant in at least one diet are shown (<5% false discovery rate).

Figure 3

Figure 3

Overfeeding-induced changes in individual plasma ceramides in the groups. Each square in the heat map indicates the log2 of the ratio between mean concentrations after vs. before for an individual ceramide. The color key denotes the relationship between the color of the heat map and log2 of the ratio between the means, with 0 indicating no change. The _y_-axis denotes the fatty acyl chain structure (number of carbon atoms:number of double bonds), and the _x_-axis indicates the sphingoid base species. *P < 0.05; ***P < 0.001.

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