Lipid emulsion administered intravenously or orally attenuates triglyceride accumulation and expression of inflammatory markers in the liver of nonobese mice fed parenteral nutrition formula

Abstract

The accumulation of hepatic TG and development of hepatic steatosis (HS) is a serious complication of the use of parenteral nutrition (PN) formulas containing a high percentage of dextrose. But whether fat emulsions or other nutrients can ameliorate the induction of HS by high-carbohydrate diets is still uncertain. We hypothesized that administration of a lipid emulsion (LE; Intralipid) and/or the vitamin A metabolite retinal (RAL) will reduce hepatic TG accumulation and attenuate indicators of inflammation. C57BL/6 male mice were fed PN formula as their only source of hydration and nutrition for 4-5 wk. In Expt. 1, mice were fed PN only or PN plus treatment with RAL (1 μg/g orally), LE (200 μL i.v.), or both LE and RAL. In Expt. 2, LE was orally administered at 4 and 13.5% of energy to PN-fed mice. All PN mice developed HS compared with mice fed normal chow (NC) and HS was reduced by LE. The liver TG mass was lower in the PN+LE and PN+RAL+LE groups compared with the PN and PN+RAL groups (P < 0.01) and in the 4% and 13.5% PN+LE groups compared with PN alone. Hepatic total retinol was higher in the RAL-fed mice (P < 0.0001), but RAL did not alter TG mass. mRNA transcripts for fatty acid synthase (Fasn) and sterol regulatory element-binding protein-1c (Srebpf1) were higher in the PN compared with the NC mice, but FAS protein and Srebpf1 mRNA were lower in the PN+LE groups compared with PN alone. The inflammation marker serum amyloid P component was also reduced. In summary, LE given either i.v. or orally may be sufficient to reduce the steatotic potential of orally fed high-dextrose formulas and may suppress the early development of HS during PN therapy.

FIGURE 1

Histology of liver from mice administered PN formula with or without RAL and LE treatments. (A) H-E staining of formalin-fixed, paraffin-embedded sections and (B) Oil Red O staining of frozen liver sections with hematoxylin counter staining (Expt. 1). Sections from liver of mice fed NC serves as a reference for normal histology and Oil Red O staining. (C) H-E and Oil Red O staining of liver sections (Expt. 2). Red: lipid; purple: nuclei. Original magnification ×100. Representative images from each group (n = 6–9) are shown. H-E, hematoxylin and eosin; LE, lipid emulsion; NC, normal chow; PN, parenteral nutrition diet; RAL, retinal.

FIGURE 2

Liver TG concentration in mice administered PN formula with or without RAL and LE treatments in Expt. 1 (A) and 2 (B). Data shown are for individual mice with mean (wide bar) and SEM (narrow bars) for each group. Mean ± SEM, n = 7–9 (Expt. 1) or 5 (Expt. 2). *Different from PN, P < 0.001. PN-fed groups without a common letter differ, P < 0.05. LE, lipid emulsion; NC, normal chow; PN, parenteral nutrition diet; RAL, retinal.

FIGURE 3

Relative mRNA levels for FAS (Fasn) transcripts (A,B) and protein (C) and SREBP1c (Srebpf1) transcripts (D,E) in the liver of mice administered PN formula with or without RAL and LE treatments in Expt. 1 (A,D) and 2 (B,C,E). The mean of the NC group was set to 1.0. Values are mean ± SEM, n = 7–9 (Expt. 1) or 5 (Expt. 2). *Different from PN, P < 0.05. PN-fed groups without a common letter differ, P < 0.05. LE, lipid emulsion; NC, normal chow; PN, parenteral nutrition diet; RAL, retinal.

FIGURE 4

Relative mRNA levels for inflammatory markers Ccl2 and Apcs in the liver of PN-fed mice administered PN formula with or without RAL and LE treatments in Expt. 1 (A) and 2 (B). Values are mean ± SEM, n = 7–9 (Expt. 1) or 5 (Expt. 2). *Different from PN, P < 0.005. PN-fed groups without a common letter differ, P < 0.05. LE, lipid emulsion; NC, normal chow; PN, parenteral nutrition diet; RAL, retinal.

FIGURE 5

Epididymal adipose tissue weight, cell number, and cellularity in PN-fed mice. Adipose tissue weight per BW in Expt. 1 (A) and Expt. 2 (B). Values are mean ± SEM, n = 7–9 (Expt. 1) or 5 (Expt. 2). *Different from PN, P < 0.05. PN-fed groups without a common letter differ, P < 0.05. (C) Adipocyte size (Expt. 1). (D) Representative H-E–stained adipose sections (Expt. 2). BW, body weight; H-E, hematoxylin and eosin; LE, lipid emulsion; NC, normal chow; PN, parenteral nutrition diet; RAL, retinal.