Metabolic adaptations to dietary fat malabsorption in chylomicron-deficient mice

Jung, Hye Rim; Turner, Scott; Neese, Richard A.; Young, Stephen G.; Hellerstein, Marc K.

doi:10.1042/0264-6021:3430473

Cited by 16 publications

(9 citation statements)

References 9 publications

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“…, around 70% [18]. We and others [16], [20]–[22] have avoided this issue by using protocols that result in a moderate precursor pool labelling of ∼15%.…”

Section: Discussionmentioning

confidence: 97%

High Fat Feeding Induces Hepatic Fatty Acid Elongation in Mice

et al. 2009

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BackgroundHigh-fat diets promote hepatic lipid accumulation. Paradoxically, these diets also induce lipogenic gene expression in rodent liver. Whether high expression of these genes actually results in an increased flux through the de novo lipogenic pathway in vivo has not been demonstrated.Methodology/Principal FindingsTo interrogate this apparent paradox, we have quantified de novo lipogenesis in C57Bl/6J mice fed either chow, a high-fat or a n-3 polyunsaturated fatty acid (PUFA)-enriched high-fat diet. A novel approach based on mass isotopomer distribution analysis (MIDA) following 1-13C acetate infusion was applied to simultaneously determine de novo lipogenesis, fatty acid elongation as well as cholesterol synthesis. Furthermore, we measured very low density lipoprotein-triglyceride (VLDL-TG) production rates. High-fat feeding promoted hepatic lipid accumulation and induced the expression of lipogenic and cholesterogenic genes compared to chow-fed mice: induction of gene expression was found to translate into increased oleate synthesis. Interestingly, this higher lipogenic flux (+74 µg/g/h for oleic acid) in mice fed the high-fat diet was mainly due to an increased hepatic elongation of unlabeled palmitate (+66 µg/g/h) rather than to elongation of de novo synthesized palmitate. In addition, fractional cholesterol synthesis was increased, i.e. 5.8±0.4% vs. 8.1±0.6% for control and high fat-fed animals, respectively. Hepatic VLDL-TG production was not affected by high-fat feeding. Partial replacement of saturated fat by fish oil completely reversed the lipogenic effects of high-fat feeding: hepatic lipogenic and cholesterogenic gene expression levels as well as fatty acid and cholesterol synthesis rates were normalized.Conclusions/SignificanceHigh-fat feeding induces hepatic fatty acid synthesis in mice, by chain elongation and subsequent desaturation rather than de novo synthesis, while VLDL-TG output remains unaffected. Suppression of lipogenic fluxes by fish oil prevents from high fat diet-induced hepatic steatosis in mice.

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“…, around 70% [18]. We and others [16], [20]–[22] have avoided this issue by using protocols that result in a moderate precursor pool labelling of ∼15%.…”

Section: Discussionmentioning

confidence: 97%

High Fat Feeding Induces Hepatic Fatty Acid Elongation in Mice

et al. 2009

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“…[ 13 C 4 ]palmitate was prepared by dissolving its potassium salt in saline and complexing with 20% wt/vol albumin solution at 40°C. In initial studies, a stock solution was diluted so that infusion at 5 μl/min provided 0.271 μmol·kg −1 ·min −1 tracer (1, 20). Following preliminary analysis, the concentration was later increased so that the infusion delivered 0.542 μmol·kg −1 ·min −1 to increase tissue enrichment.…”

Section: Methodsmentioning

confidence: 99%

“…Calculated kinetic results were similar in both groups, so data were combined for statistical analysis. Following a 4-h fast, the tracer infusion was commenced using a Harvard apparatus syringe pump (World Precision Instruments, Stevenage, UK) for 180 min (20). Animals were euthanized by decapitation within 60 s of being disturbed, and trunk blood was collected on wet ice.…”

Section: Methodsmentioning

confidence: 99%

“…2 (1, 8, 20):

Fraction of TG palmitate derived from plasma FFA = IE of [^{13} {normalC}_{4}] palmitate in TG palmitate / IE of [^{13} {normalC}_{4}] palmitate in plasma .

The absolute contribution of circulating palmitate to tissue or plasma TGs was calculated by correcting for the TG pool size using Eq. 3 :

Absolute palmitate uptake = fraction of TG palmitate derived from plasma \times TG poolsize,

where tissue and plasma TG pool sizes were calculated by multiplying TG concentration by tissue weight [assuming adipose tissue to be composed of pure TG of molecular weight 861 (14)] or estimated plasma volume [3.5% of body weight (18)], respectively.…”

Section: Methodsmentioning

confidence: 99%

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Metabolic pathways promoting intrahepatic fatty acid accumulation in methionine and choline deficiency: implications for the pathogenesis of steatohepatitis

Macfarlane¹,

Zou²,

Andrew³

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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The pathological mechanisms that distinguish simple steatosis from steatohepatitis (or NASH, with consequent risk of cirrhosis and hepatocellular cancer) remain incompletely defined. Whereas both a methionine- and choline-deficient diet (MCDD) and a choline-deficient diet (CDD) lead to hepatic triglyceride accumulation, MCDD alone is associated with hepatic insulin resistance and inflammation (steatohepatitis). We used metabolic tracer techniques, including stable isotope ([13C4]palmitate) dilution and mass isotopomer distribution analysis (MIDA) of [13C2]acetate, to define differences in intrahepatic fatty acid metabolism that could explain the contrasting effect of MCDD and CDD on NASH in C57Bl6 mice. Compared with control-supplemented (CS) diet, liver triglyceride pool sizes were similarly elevated in CDD and MCDD groups (24.37 ± 2.4, 45.94 ± 3.9, and 43.30 ± 3.5 μmol/liver for CS, CDD, and MCDD, respectively), but intrahepatic neutrophil infiltration and plasma alanine aminotransferase (31 ± 3, 48 ± 4, 231 ± 79 U/l, P < 0.05) were elevated only in MCDD mice. However, despite loss of peripheral fat in MCDD mice, neither the rate of appearance of palmitate (27.2 ± 3.5, 26.3 ± 2.3, and 28.3 ± 3.5 μmol·kg−1·min−1) nor the contribution of circulating fatty acids to the liver triglyceride pool differed between groups. Unlike CDD, MCDD had a defect in hepatic triglyceride export that was confirmed using intravenous tyloxapol (142 ± 21, 122 ± 15, and 80 ± 7 mg·kg−1·h−1, P < 0.05). Moreover, hepatic de novo lipogenesis was significantly elevated in the MCDD group only (1.4 ± 0.3, 2.3 ± 0.4, and 3.4 ± 0.4 μmol/day, P < 0.01). These findings suggest that important alterations in hepatic fatty acid metabolism may promote the development of steatohepatitis. Similar mechanisms may predispose to hepatocyte damage in human NASH.

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“…The isotope dilution technique as well as the preparation of plasma samples for analysis of bile salts by gas chromatography/mass spectrometry (GC/MS) were described in detail by Hulzebos et al23 Fecal neutral sterols were analyzed as described 24. Labeling of acetyl‐coenzyme A pools with orally provided [1‐ 13 C]‐acetate was described by Jung et al25 Cholesterol was extracted from blood spots and prepared for GC/MS analysis as described 26. Lipids in liver homogenates were hydrolyzed in HCl/acetonitril.…”

Section: Methodsmentioning

confidence: 99%

Bile salt sequestration induces hepaticde novolipogenesis through farnesoid X receptor- and liver X receptorα-controlled metabolic pathways in mice

et al. 2010

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Diabetes is characterized by high blood glucose levels and dyslipidemia. Bile salt sequestration has been found to improve both plasma glycemic control and cholesterol profiles in diabetic patients. Yet bile salt sequestration is also known to affect triglyceride (TG) metabolism, possibly through signaling pathways involving farnesoid X receptor (FXR) and liver X receptor ␣ (LXR␣). We quantitatively assessed kinetic parameters of bile salt metabolism in lean C57Bl/6J and in obese, diabetic db/db mice upon bile salt sequestration using colesevelam HCl (2% wt/wt in diet) and related these to quantitative changes in hepatic lipid metabolism. As expected, bile salt sequestration reduced intestinal bile salt reabsorption. Importantly, bile salt pool size and biliary bile salt secretion remained unchanged upon sequestrant treatment due to compensation by de novo bile salt synthesis in both models. Nevertheless, lean and db/db mice showed increased, mainly periportally confined, hepatic TG contents, increased expression of lipogenic genes, and increased fractional contributions of newly synthesized fatty acids. D iabetes is a multifactorial disease characterized by increased fasting blood glucose levels and dyslipidemia-that is, high plasma triglyceride (TG) and low-density lipoprotein cholesterol levels. Controlling blood glucose and cholesterol levels in diabetic patients is critical for delaying the progression of clinical complications such as neuropathy and cardiovascular disease. An efficient way to reduce plasma cholesterol levels is to induce cholesterol secretion in bile, either as bile salt or as free cholesterol. Bile is secreted into the ileum to facilitate absorption of lipids and lipid-soluble vitamins. About 95% of secreted bile salts are reabsorbed in the terminal ileum and transported back to the liver through the portal vein (enterohepatic circulation). In addition to their function in the absorption of dietary fats, bile salts are signaling molecules that play an important role in the regulation of lipid metabolism. 1 Interestingly, bile salt metabolism is affected in diabetes, which might contribute to the altered lipid profile observed in diabetic patients. 2 Knowledge of potential disturbances in bile salt metabolism in type 2 diabetic humans and animal models is still very limited, however. 3 Increasing fecal bile salt loss by preventing their intestinal reabsorption (sequestration) increases bile salt synthesis and, hence, hepatic cholesterol turnover. As a consequence, low-density lipoprotein cholesterol levels

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Metabolic adaptations to dietary fat malabsorption in chylomicron-deficient mice

Cited by 16 publications

References 9 publications

High Fat Feeding Induces Hepatic Fatty Acid Elongation in Mice

High Fat Feeding Induces Hepatic Fatty Acid Elongation in Mice

Metabolic pathways promoting intrahepatic fatty acid accumulation in methionine and choline deficiency: implications for the pathogenesis of steatohepatitis

Bile salt sequestration induces hepaticde novolipogenesis through farnesoid X receptor- and liver X receptorα-controlled metabolic pathways in mice

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