Lipid Emulsions, Rich in n‐3 or n‐9 Fatty Acids, Reverse the Progression of Parenteral Nutrition‐Induced Hepatic Steatosis in Mice
Authors: HUANG KUAN‐HSUN , Smith Philip B. , Patterson Andrew D. , Ross A. Catharine 
Published: November 2023

Hepatic steatosis occurs in the early stage of the parenteral nutrition (PN)‐associated liver disease. Our previous study showed that Intralipid®, a lipid emulsion (LE) rich in n‐6 fatty acids (FA), reduced hepatic triacylglycerol (TG) accumulation and markers of inflammation, once lipid accumulation has begun. However, it remains unclear whether other LEs (Omegaven®, rich in n‐3 FA, and ClinOleic®, rich in n‐9 FA), can reverse hepatic steatosis. Here, we tested the hypothesis that Omegaven® and ClinOleic® administration will reverse hepatic TG accumulation, while regulating lipogenic genes and lipid metabolism, after the onset of steatosis.

Methods

Male C57BL/6 mice were fed chow (a reference group for normal mouse diet) for 5 weeks or PN diet (Clinimix‐E® supplemented with vitamins and minerals and containing 3% Intralipid® to ensure adequacy of essential FA) for 2.5 weeks (PN2.5) to develop hepatic steatosis. At this time, mice were randomized into 4 groups: continuation of PN alone (PN5), or change to PN with 13.5% (en‐%) of either Omegaven® (FOLE), ClinOleic® (OOLE), or Intralipid® (SOLE) for an additional 2.5 weeks (n= 8–9/group). The levels of lipogenic genes, lipid mobilization‐associated genes, and total FA composition were analyzed using one‐way ANOVA, followed by Fisher's test.

Results

FOLE and OOLE mice had lower liver TG levels at wk 5 compared to PN2.5 and PN5 mice (all P<0.01), while the mice fed SOLE had less hepatic TG content, as compared to PN5 mice (P<0.01). FOLE mice had lower hepatic TG, not different from the chow group. FOLE mice had the lowest levels of transcripts for lipogenesis‐associated genes including ATP‐citrate lyase (Cly), acetyl‐CoA carboxylase‐1 (Acc1), fatty acid synthase (Fas), and stearoyl‐CoA desaturase‐1 (Scd‐1), as well as sterol regulatory element‐binding protein‐1c (Srebpf1), peroxisome proliferator‐activated receptor‐α (Ppar‐α), and Ppar‐γ (all P<0.001). Gas chromatography‐mass spectrometry (GC‐MS) data revealed that FOLE, OOLE, and SOLE mice had lower levels of palmitic acid, palmitoleic acid, and vaccenic acid, and FOLE had the lowest level of arachidonic acid but highest levels of docosahexaenoic acid and eicosapentaenoic acid in liver, as compared to PN2.5 and PN5 mice (all P<0.001). The expression of genes involved in lipid mobilization were also reduced in FOLE mice, including peroxisomal acyl‐CoA oxidase‐1 (Acox1), mitochondrial carnitine palmitoyltransferase‐I (Cpt‐1), acyl‐CoA dehydrogenase (Acad1), and microsomal triglyceride transfer protein (Mttp) (all P<0.0001), while OOLE and SOLE mice had lower Acox1 (P<0.001). In conclusion, by including 13.5 en‐% of LE rich in n‐9 and n‐3 FA into the PN formula the progression of lipid accumulation in mice was reversed with preexisting PN‐induced steatosis, concurrent with alterations in lipogenesis, total FA composition, and lipid oxidation.

Support or Funding Information

Baxter provided materials used in this research.