Relationships between fatty acid synthesis and lipid secretion in the isolated perfused rat liver: Effects of hyperthyroidism, glucose and oleate

Castellani, Lawrence W.; Wilcox, Henry C.; Heimberg, Murray

doi:10.1016/0005-2760(91)90008-6

Cited by 12 publications

(8 citation statements)

References 57 publications

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“…Media and tissue were then collected and total lipids extracted as described above. Total lipid isolates were then hydrolyzed in an acid/acetonitrile solution as described previously, and the lipids were re-extracted and dried under nitrogen (55). The sample was then separated by TLC and radioactivity in the fatty acid fraction determined by liquid scintillation spectrometry (55).…”

Section: Methodsmentioning

confidence: 99%

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Apolipoprotein AII Is a Regulator of Very Low Density Lipoprotein Metabolism and Insulin Resistance

Castellani

Nguyen

Charugundla

et al. 2008

Journal of Biological Chemistry

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Apolipoprotein AII (apoAII) transgenic (apoAIItg) mice exhibit several traits associated with the insulin resistance (IR) syndrome, including IR, obesity, and a marked hypertriglyceridemia. Because treatment of the apoAIItg mice with rosiglitazone ameliorated the IR and hypertriglyceridemia, we hypothesized that the hypertriglyceridemia was due largely to overproduction of very low density lipoprotein (VLDL) by the liver, a normal response to chronically elevated insulin and glucose. We now report in vivo and in vitro studies that indicate that hepatic fatty acid oxidation was reduced and lipogenesis increased, resulting in a 25% increase in triglyceride secretion in the apoAIItg mice. In addition, we observed that hydrolysis of triglycerides from both chylomicrons and VLDL was significantly reduced in the apoAIItg mice, further contributing to the hypertriglyceridemia. This is a direct, acute effect, because when mouse apoAII was injected into mice, plasma triglyceride concentrations were significantly increased within 4 h. VLDL from both control and apoAIItg mice contained significant amounts of apoAII, with ϳ4 times more apoAII on apoAIItg VLDL. ApoAII was shown to transfer spontaneously from high density lipoprotein (HDL) to VLDL in vitro, resulting in VLDL that was a poorer substrate for hydrolysis by lipoprotein lipase. These results indicate that one function of apoAII is to regulate the metabolism of triglyceride-rich lipoproteins, with HDL serving as a plasma reservoir of apoAII that is transferred to the triglyceride-rich lipoproteins in much the same way as VLDL and chylomicrons acquire most of their apoCs from HDL.More than 95% of plasma apolipoprotein AII (apoAII) 2 is associated with high density lipoproteins (HDLs) where it is the second most abundant protein comprising ϳ20% of the HDL total protein mass (1). Studies of the physiologic effects of apoAII have focused on reverse cholesterol transport and antioxidant functions, mechanisms through which HDLs are believed to protect against atherosclerosis (2, 3). Most but not all of these studies suggest that increased apoAII impaired both of these processes and promoted atherosclerosis (4 -8). Additional evidence for other physiologic effects of apoAII has come from genetic studies in both humans and mice, which suggest a role for apoAII in triglyceride and free fatty acid metabolism (8 -10). Subsequently, studies of genetically modified mice carrying a transgene for either human or mouse apoAII (3, 11-21), as well as apoAII knockout mice (22), confirmed a complex metabolic role for apoAII, including a rather profound effect on plasma triglyceride concentrations.Hypertriglyceridemia is an integral component of the phenotype of several disease states, including type 2 diabetes, familial combined hyperlipidemia, and the metabolic syndrome, and it is likely to be one of several contributing factors underlying the increased atherosclerosis associated with these complex diseases. Hypertriglyceridemia has been demonstrated to be an independent risk factor ...

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Section: Methodsmentioning

confidence: 99%

“…Total lipids were extracted using the method of Folch et al (54). Following extraction, the lipid classes were separated by TLC, and the radioactivity in the triglyceride fraction was determined by liquid scintillation spectrometry (55). Radioactivity in media triglycerides represents VLDL secretion.…”

Section: Methodsmentioning

confidence: 99%

Apolipoprotein AII Is a Regulator of Very Low Density Lipoprotein Metabolism and Insulin Resistance

Castellani

Nguyen

Charugundla

et al. 2008

Journal of Biological Chemistry

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“…The hepatocytes were washed thrice with cold PBS and then collected for lipid extraction. The major lipid classes (phospholipids, cholesterol, unesterified fatty acids, triglycerides, and cholesteryl esters) were extracted (Folch et al 1957) and separated by thin layer chromatography, and the radioactivity incorporated into the triglyceride fraction was determined by liquid scintillation spectrometry as described (Castellani et al 1991).…”

Section: Lipid Analysismentioning

confidence: 99%

Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR

Zhang¹,

Castellani²,

Sinal³

et al. 2004

Genes Dev.

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330

261

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Peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC-1␣) has been shown to regulate adaptive thermogenesis and glucose metabolism. Here we show that PGC-1␣ regulates triglyceride metabolism through both farnesoid X receptor (FXR)-dependent and -independent pathways. PGC-1␣ increases FXR activity through two pathways: (1) it increases FXR mRNA levels by coactivation of PPAR␥ and HNF4␣ to enhance FXR gene transcription; and (2) it interacts with the DNA-binding domain of FXR to enhance the transcription of FXR target genes. Ectopic expression of PGC-1␣ in murine primary hepatocytes reduces triglyceride secretion by a process that is dependent on the presence of FXR. Consistent with these in vitro studies, we demonstrate that fasting induces hepatic expression of PGC-1␣ and FXR and results in decreased plasma triglyceride levels in wild-type but not in FXR-null mice. Our data suggest that PGC-1␣ plays an important physiological role in maintaining energy homeostasis during fasting by decreasing triglyceride production/ secretion while it increases fatty acid ␤-oxidation to meet energy needs.

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“…Insulin and triiodothyronine (T 3 ) are involved in mediating the effects of diet on lipogenesis in vivo (34). Hepatic lipogenesis is increased in hyperthyroid states or in response to T 3 injection (10,15,19,24,25,28,62,71,76,83) as well as in hyperinsulinemic subjects (80). In vivo, these two hormones are also involved in the long-term regulation of lipogenic enzymes activities such as fatty acid synthase (37).…”

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confidence: 99%

Hepatic regulation of fatty acid synthase by insulin and T₃: evidence for T₃genomic and nongenomic actions

Radenne¹,

Akpa²,

Martel³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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is a key enzyme of hepatic lipogenesis responsible for the synthesis of long-chain saturated fatty acids. This enzyme is mainly regulated at the transcriptional level by nutrients and hormones. In particular, glucose, insulin, and T 3 increase FAS activity, whereas glucagon and saturated and polyunsaturated fatty acids decrease it. In the present study we show that, in liver, T 3 and insulin were able to activate FAS enzymatic activity, mRNA expression, and gene transcription. We localized the T 3 response element (TRE) that mediates the T3 genomic effect, on the FAS promoter between Ϫ741 and Ϫ696 bp that mediates the T 3 genomic effect. We show that both T3 and insulin regulate FAS transcription via this sequence. The TRE binds a TR/RXR heterodimer even in the absence of hormone, and this binding is increased in response to T 3 and/or insulin treatment. The use of H7, a serine/threonine kinase inhibitor, reveals that a phosphorylation mechanism is implicated in the transcriptional regulation of FAS in response to both hormones. Specifically, we show that T 3 is able to modulate FAS transcription via a nongenomic action targeting the TRE through the activation of a PI 3-kinase-ERK1/2-MAPK-dependent pathway. Insulin also targets the TRE sequence, probably via the activation of two parallel pathways: Ras/ERK1/2 MAPK and PI 3-kinase/Akt. Finally, our data suggest that the nongenomic actions of T 3 and insulin are probably common to several TREs, as we observed similar effects on a classical DR4 consensus sequence. fatty acid synthase; triiodothyronine; insulin; triiodothyronine response element; phosphoinositide 3-kinase; extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase LIPOGENESIS CONVERTS DIETARY CARBOHYDRATES to fatty acids primarily in liver (28). Insulin and triiodothyronine (T 3 ) are involved in mediating the effects of diet on lipogenesis in vivo (34). Hepatic lipogenesis is increased in hyperthyroid states or in response to T 3 injection (10,15,19,24,25,28,62,71,76,83) as well as in hyperinsulinemic subjects (80). In vivo, these two hormones are also involved in the long-term regulation of lipogenic enzymes activities such as fatty acid synthase (37).Fatty acid synthase (FAS; EC.2.3.1.85) is a key enzyme in hepatic lipogenesis. In the presence of NADPH, this multifunctional enzyme catalyzes the conversion of acetyl-CoA and malonyl-CoA into long-chain saturated fatty acids such as palmitate and stearate (92). The de novo synthesis of fatty acids in human and chicken takes place mainly in the liver (30, 58), whereas in rodents the adipose tissue is also lipogenic (30). In vertebrates, FAS is a homodimer made of two identical peptide chains of ϳ260 kDa (85, 91), located in the cytoplasm of the cell (31). FAS is encoded by a unique gene that generates only one mRNA in mouse (73) and two in chicken and rat, as a result of alternative splicing (3). In the liver, the activity of FAS, like most lipogenic enzymes (95), is regulated through nutrients and hormones. Starvation causes a decrea...

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Relationships between fatty acid synthesis and lipid secretion in the isolated perfused rat liver: Effects of hyperthyroidism, glucose and oleate

Cited by 12 publications

References 57 publications

Apolipoprotein AII Is a Regulator of Very Low Density Lipoprotein Metabolism and Insulin Resistance

Apolipoprotein AII Is a Regulator of Very Low Density Lipoprotein Metabolism and Insulin Resistance

Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR

Hepatic regulation of fatty acid synthase by insulin and T₃: evidence for T₃genomic and nongenomic actions

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Relationships between fatty acid synthesis and lipid secretion in the isolated perfused rat liver: Effects of hyperthyroidism, glucose and oleate

Cited by 12 publications

References 57 publications

Apolipoprotein AII Is a Regulator of Very Low Density Lipoprotein Metabolism and Insulin Resistance

Apolipoprotein AII Is a Regulator of Very Low Density Lipoprotein Metabolism and Insulin Resistance

Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR

Hepatic regulation of fatty acid synthase by insulin and T3: evidence for T3genomic and nongenomic actions

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Hepatic regulation of fatty acid synthase by insulin and T₃: evidence for T₃genomic and nongenomic actions