Proline and hepatic lipogenesis

Sugden, Mary C.; Watts, David; West, Peter; Palmer, T.N.

doi:10.1016/0304-4165(84)90111-9

Cited by 10 publications

(7 citation statements)

References 16 publications

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“…Sources of cytosolic acetyl-CoA not derived from ATP citrate-lyase (see above) or an overestimation of the extent of inhibition of ATP citrate-lyase, based on the [1,5-'4C]citrate experiments, may underly these findings. The less efficient inhibition of fatty acid synthesis than of cholesterol synthesis in the 3H20 experiments may be explained by allosteric stimulation of acetyl-CoA carboxylase activity by (-)-hydroxycitrate, as shown by Sugden et al (1984) and Triscari & Sullivan (1977).…”

Section: Discussionmentioning

confidence: 94%

The effect of (−)-hydroxycitrate on the activity of the low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levels in the human hepatoma cell line Hep G2

Berkhout¹,

Havekes²,

Pearce³

et al. 1990

Biochemical Journal

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(-)-Hydroxycitrate, a potent inhibitor of ATP citrate-lyase, was tested in Hep G2 cells for effects on cholesterol homoeostasis. After 2.5 h and 18 h incubations with (-)-hydroxycitrate at concentrations of 0.5 mM or higher, incorporation of [1,5-14C]citrate into fatty acids and cholesterol was strongly inhibited. This most likely reflects an effective inhibition of ATP citrate-lyase. Cholesterol biosynthesis was decreased to 27% of the control value as measured by incorporations from 3H2O, indicating a decreased flux of carbon units through the cholesterol-synthetic pathway. After 18 h preincubation with 2 mM-(-)-hydroxycitrate, the cellular low-density-lipoprotein (LDL) receptor activity was increased by 50%, as determined by the receptor-mediated association and degradation. Measurements of receptor-mediated binding versus LDL concentration suggests that this increase was due to an increase in the numbers of LDL receptors. Simultaneously, enzyme levels of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase as determined by activity measurements increased 30-fold. Our results suggest that the increases in HMG-CoA reductase and the LDL receptor are initiated by the decreased flux of carbon units in the cholesterol-synthetic pathway, owing to inhibition of ATP citratelyase. A similar induction of HMG-CoA reductase and LDL receptor was also found after preincubations of cells with 0.3 microM-mevinolin, suggesting that the underlying mechanism for this induction is identical for both drugs.

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Section: Discussionmentioning

confidence: 94%

The effect of (−)-hydroxycitrate on the activity of the low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levels in the human hepatoma cell line Hep G2

Berkhout¹,

Havekes²,

Pearce³

et al. 1990

Biochemical Journal

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“…The approach-to-steady state and maximal levels of albumin and transferrin secretion were shown to be dependent on L-proline concentration (11). In other hepatocyte culture systems, proline has been shown to affect lipogenesis, glycogen synthesis, and cell proliferation (12)(13)(14)(15). In an effort to understand the mechanism responsible for this response to proline, we investigated in more detail the relationship between proline and hepatocyte function in sandwich cultures.…”

mentioning

confidence: 99%

Proline‐mediated enhancement of hepatocyte function in a collagen gel sandwich culture configuration

et al. 1993

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Isolated rat primary hepatocytes were cultured between two layers of gelled collagen in a sandwich configuration that reinstates the cellular polarity necessary for long-term function in vitro. Maintenance of hepatocyte function, as measured by the secretion of albumin, was shown to be dependent on both the sandwich gel configuration and the continued presence of L-proline in the culture media. Cis-hydroxyproline, an analog of proline known to prevent the proper folding of triple helical collagen molecules, inhibited the response of sandwiched hepatocytes to proline in a dose-dependent and reversible manner. The addition of cis-hydroxyproline to cultures established for 7 days also resulted in the inhibition of hepatocyte function. These data support the hypothesis that continued collagen synthesis by hepatocytes is critical for hepatocyte function in the sandwich gel configuration.

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“…The hepatic levels of amino acids and organic acids were also analyzed after chronic T3 and T3 withdrawal (Supplementary Table S2). Interestingly, T3 withdrawal significantly increased hepatic lactate, an established lipogenic precursor (17).…”

Section: Adaptations During Hyperthyroidism and Withdrawal 855mentioning

confidence: 98%

“…6B), suggesting that the lipogenesis pathway was indeed activated. Increased lactate is an established lipogenic precursor (17) and was increased in the liver. There also was a trend toward increased triglyceride concentration, consistent with the lipogenic pathway being activated functionally.…”

Section: Adaptations During Hyperthyroidism and Withdrawal 857mentioning

confidence: 99%

Changes in Hepatic TRβ Protein Expression, Lipogenic Gene Expression, and Long-Chain Acylcarnitine Levels During Chronic Hyperthyroidism and Triiodothyronine Withdrawal in a Mouse Model

Ohba

Sinha

Singh

et al. 2017

Thyroid

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Background: Thyroid hormone (TH) has important roles in regulating hepatic metabolism. It was previously reported that most hepatic genes activated by a single triiodothyronine (T3) injection became desensitized after multiple injections, and that approximately 10% of target genes did not return to basal expression levels after T3 withdrawal, despite normalization of serum TH and thyrotropin (TSH) levels. To determine the possible mechanism(s) for desensitization and incomplete recovery of hepatic target gene transcription and their effects on metabolism, mRNA and/or protein expression levels of key regulators of TH action were measured, as well as metabolomic changes after chronic T3 treatment and withdrawal. Methods: Adult male mice were treated with daily injections of T3 (20 lg/100 g body weight) for 14 days followed by the cessation of T3 for 10 days. Livers were harvested at 6 hours, 24 hours, and 14 days after the first T3 injection, and at 10 days after withdrawal, and then analyzed by quantitative reverse transcription polymerase chain reaction, Western blotting, and metabolomics. Results: Although TH receptor (TRa and TRb) mRNAs decreased slightly after chronic T3 treatment, only TRb protein decreased before returning to basal expression level after withdrawal. The expression of other regulators of TH action was unchanged. TRb protein expression was also decreased in adult male monocarboxylate transporter-8 (Mct8)-knockout mice, an in vivo model of chronic intrahepatic hyperthyroidism. Previously, increased hepatic long-chain acylcarnitine levels were found after acute TH treatment. However, in this study, long-chain acylcarnitine levels were unchanged after chronic T3, and paradoxically increased after T3 withdrawal. Pathway analyses of the previous microarray results showed upregulation of lipogenic genes after acute T3 treatment and withdrawal. Phosphorylation of acetyl-CoA carboxylase also decreased after T3 withdrawal. Conclusions: Decreased hepatic TRb protein expression occurred after chronic T3 exposure in adult male wild-type and Mct8-knockout mice. Gene array pathway and metabolomics analyses showed abnormalities in hepatic lipogenic gene expression and acylcarnitine levels, respectively, after withdrawal, despite normalization of serum TSH and TH levels. These findings may help explain the variable clinical presentations of some patients during hyperthyroidism and recovery, since TRb protein, target gene expression, and metabolic adaptive changes can occur in individual tissues without necessarily being reflected by circulating TH and TSH concentrations.

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Proline and hepatic lipogenesis

Cited by 10 publications

References 16 publications

The effect of (−)-hydroxycitrate on the activity of the low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levels in the human hepatoma cell line Hep G2

The effect of (−)-hydroxycitrate on the activity of the low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levels in the human hepatoma cell line Hep G2

Proline‐mediated enhancement of hepatocyte function in a collagen gel sandwich culture configuration

Changes in Hepatic TRβ Protein Expression, Lipogenic Gene Expression, and Long-Chain Acylcarnitine Levels During Chronic Hyperthyroidism and Triiodothyronine Withdrawal in a Mouse Model

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