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

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.

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

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

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.