Lipid Emulsion Added to a Liquid High-Carbohydrate Diet and Voluntary Running Exercise Reduce Lipogenesis and Ameliorate Early-Stage Hepatic Steatosis in Mice.

Background: The use of parenteral nutrition formulas is often associated with the development of hepatic steatosis. We have shown previously that the addition of a lipid emulsion (LE) rich in n-6 (ω-6) fatty acids (FAs) ameliorated triglyceride (TG) accumulation in the livers of nonobese mice fed a high-carbohydrate diet (HCD) for 5 wk. However, it remains unclear how rapidly this condition develops and whether it can be prevented by LE with or without a running wheel for voluntary exercise (Exe).Objective: We investigated in an 8-d study whether mice develop steatosis and whether the administration of LE with or without Exe reduces the concentration of total FAs and prevents an increase in the expression of genes in the liver associated with lipogenesis.Methods: Male C57BL/6 mice aged 5 wk were randomized into 5 groups: standard feed pellet (SFP); a liquid HCD (77% of total energy from carbohydrates and 0.5% from fat); HCD + Exe; HCD + 13.5% LE (67% carbohydrates and 13.5% fat); or HCD + 13.5% LE + Exe. Hepatic TG concentration, lipogenic genes, and total FAs were measured on day 8.Results: Oil Red O staining and TG quantification showed hepatic TG accumulation on day 8; the addition of 13.5% LE either with or without Exe suppressed the TG accumulation compared with HCD (P < 0.005). With the use of quantitative reverse transcriptase-polymerase chain reaction analysis, the expression concentrations of lipogenic genes [ATP-citrate lyase, acetyl coenzyme A carboxylase 1, FA synthase (Fasn), and stearoyl coenzyme A desaturase 1 (Scd1)] in the HCD + 13.5% LE group were 26-60% of HCD (P < 0.01) and 11-38% of HCD in the HCD + 13.5% LE + Exe group (P < 0.001), with interactions for Fasn and Scd1 (P < 0.05). With the use of gas chromatography-mass spectrometry analysis, the HCD + 13.5% LE group had lower monounsaturated fatty acids (38.7% of HCD) but higher polyunsaturated fatty acids (164% of HCD) (P < 0.001).Conclusions: In short-term studies designed to resemble the early dynamic stage of the development of hepatic steatosis, the addition of 13.5% LE to a liquid HCD reduced hepatic lipogenesis. Exe exerted an independent protective effect and interacted with LE to further reduce the expression of Scd1.

Huang KH ，Hao L ，Smith PB ，Rogers CJ ，Patterson AD ，Ross AC ... -  《-》

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

Ito K ，Hao L ，Wray AE ，Ross AC ... -  《-》

Fibroblast Growth Factor 21 (Fgf21) Gene Expression Is Elevated in the Liver of Mice Fed a High-Carbohydrate Liquid Diet and Attenuated by a Lipid Emulsion but Is Not Upregulated in the Liver of Mice Fed a High-Fat Obesogenic Diet.

Fibroblast growth factor 21 (FGF21) is a regulator of carbohydrate and lipid metabolism; however, the regulation of Fgf21 gene expression by diet remains incompletely understood. We investigated the effect of a high-carbohydrate (HC) liquid diet, with and without supplementation with a lipid emulsion (LE), and of a high-fat diet (HFD) compared with a low-fat diet (LFD) on the regulation of Fgf21 gene expression in the liver of intact mice. C57BL/6 male mice were fed standard feed pellets (SFPs), a purified HC liquid diet (adequate in calories and protein), or an HC liquid diet containing an LE at either 4% or 13.5% of energy for 5 wk (Expt. 1) or 1 wk (Expt. 2). In Expt. 3, mice were fed a purified LFD (∼10% fat) or HFD (∼60% fat) or were fed an HFD and given access to a running wheel for voluntary exercise for 16 wk. Fgf21 mRNA in liver and FGF21 protein in plasma were increased by 3.5- to 7-fold in HC mice compared with SFP mice (P < 0.001), whereas the LE dose-dependently attenuated the induction of Fgf21 expression (P < 0.05). After 16 wk, hepatic Fgf21 mRNA did not differ between LFD and HFD mice but was dramatically reduced in the HFD+exercise group to <20% of the level in the HFD group (P < 0.0001). In mice, hepatic Fgf21 expression was upregulated by 1 and 5 wk of feeding a lipogenic HC diet but not by 16 wk of feeding an obesogenic HFD, whereas the addition of fat as an LE to the HC formula significantly reduced Fgf21 gene expression and the plasma FGF21 protein concentration. Our results support a strong and reversible response of hepatic Fgf21 expression to shifts in dietary glucose intake.

Hao L ，Huang KH ，Ito K ，Sae-Tan S ，Lambert JD ，Ross AC ... -  《-》

High hepatic SCD1 activity is associated with low liver fat content in healthy subjects under a lipogenic diet.

Silbernagel G ，Kovarova M ，Cegan A ，Machann J ，Schick F ，Lehmann R ，Häring HU ，Stefan N ，Schleicher E ，Fritsche A ，Peter A ... -  《-》

Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice.

This study investigated the effects of dietary methionine restriction (MR) on the progression of established hepatic steatosis in the leptin-deficient ob/ob mouse. Ten-week-old ob/ob mice were fed diets containing 0.86% (control-fed; CF) or 0.12% methionine (MR) for 14 weeks. At 14 weeks, liver and fat were excised and blood was collected for analysis. In another study, blood was collected to determine in vivo triglyceride (TG) and very-low-density lipoprotein (VLDL) secretion rates. Liver histology was conducted to determine the severity of steatosis. Hepatic TG, free fatty acid levels, and fatty acid oxidation (FAO) were also measured. Gene expression was analyzed by quantitative PCR. MR reversed the severity of steatosis in the ob/ob mouse. This was accompanied by reduced body weight despite similar weight-specific food intake. Compared with the CF group, hepatic TG levels were significantly reduced in response to MR, but adipose tissue weight was not decreased. MR reduced insulin and HOMA ratios but increased total and high-molecular-weight adiponectin levels. Scd1 gene expression was significantly downregulated, while Acadvl, Hadha, and Hadhb were upregulated in MR, corresponding with increased β-hydroxybutyrate levels and a trend toward increased FAO. The VLDL secretion rate was also significantly increased in the MR mice, as were the mRNA levels of ApoB and Mttp. The expression of inflammatory markers, such as Tnf-α and Ccr2, was also downregulated by MR. Our data indicate that MR reverses steatosis in the ob/ob mouse liver by promoting FAO, increasing the export of lipids, and reducing obesity-related inflammatory responses.

Malloy VL ，Perrone CE ，Mattocks DA ，Ables GP ，Caliendo NS ，Orentreich DS ，Orentreich N ... -  《-》