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Tuberous sclerosis complex-1 deficiency attenuates diet-induced hepatic lipid accumulation.

Kenerson HL, Yeh MM, Yeung RS - PLoS ONE (2011)

Bottom Line: These observations suggest that mTORC1 is neither necessary nor sufficient for steatosis.Instead, Akt and mTORC1 have opposing effects on hepatic lipid accumulation such that mTORC1 protects against diet-induced steatosis.These findings provide novel insights into the role of mTORC1 in hepatic lipid metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is causally linked to type 2 diabetes, insulin resistance and dyslipidemia. In a normal liver, insulin suppresses gluconeogenesis and promotes lipogenesis. In type 2 diabetes, the liver exhibits selective insulin resistance by failing to inhibit hepatic glucose production while maintaining triglyceride synthesis. Evidence suggests that the insulin pathway bifurcates downstream of Akt to regulate these two processes. Specifically, mTORC1 has been implicated in lipogenesis, but its role on hepatic steatosis has not been examined. Here, we generated mice with hepatocyte-specific deletion of Tsc1 to study the effects of constitutive mTORC1 activation in the liver. These mice developed normally but displayed mild hepatomegaly and insulin resistance without obesity. Unexpectedly, the Tsc1- livers showed minimal signs of steatosis even under high-fat diet condition. This 'resistant' phenotype was reversed by rapamycin and could be overcome by the expression of Myr-Akt. Moreover, rapamycin failed to reduce hepatic triglyceride levels in models of steatosis secondary to Pten ablation in hepatocytes or high-fat diet in wild-type mice. These observations suggest that mTORC1 is neither necessary nor sufficient for steatosis. Instead, Akt and mTORC1 have opposing effects on hepatic lipid accumulation such that mTORC1 protects against diet-induced steatosis. Specifically, mTORC1 activity induces a metabolic shift towards fat utilization and glucose production in the liver. These findings provide novel insights into the role of mTORC1 in hepatic lipid metabolism.

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Histologic and biochemical effects of rapamycin on HFD-induced steatosis.A) Examples of histology (H&E) and Oil Red “O” staining of the livers procured from animals described in Figure 4. NCD, normal chow diet; HFD, high-fat diet; Rapa, rapamycin. Magnification, 400X. B) Western blots of representative liver lysates from each of the four groups shown in (A) highlighting the effects of chronic rapamycin on Akt(Ser473) phosphorylation. The average ratios of band intensities (Image J) between phospho- and total-Akt are summarized in the graph (n of 5 per group).
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pone-0018075-g005: Histologic and biochemical effects of rapamycin on HFD-induced steatosis.A) Examples of histology (H&E) and Oil Red “O” staining of the livers procured from animals described in Figure 4. NCD, normal chow diet; HFD, high-fat diet; Rapa, rapamycin. Magnification, 400X. B) Western blots of representative liver lysates from each of the four groups shown in (A) highlighting the effects of chronic rapamycin on Akt(Ser473) phosphorylation. The average ratios of band intensities (Image J) between phospho- and total-Akt are summarized in the graph (n of 5 per group).

Mentions: Analysis of the livers revealed a significant increase in triglyceride levels in mice receiving HFD, and importantly, rapamycin did not alter hepatic TG levels significantly in either group of animals (Figure 4). This corroborates with the histologic findings of steatosis in the HFD-groups regardless of rapamycin treatment (Figure 5A). Further, rapamycin did not lead to any histologic change in the NCD-fed livers. Immunoblot analyses of the liver lysates showed a trend towards higher levels of Akt(Ser473) phosphorylation with HFD that were unchanged following two weeks of rapamycin (Figure 5B). Hence, despite evidence of worsening glucose intolerance, mTORC1 inhibition by rapamycin did not alter hepatic lipid content in a model of diet-induced steatosis. In contrast, the HFD-associated TG accumulation and insulin resistance reverted to baseline within 2 weeks of replacing the HFD with NCD. We conclude that mTORC1 is not necessary for the maintenance of HFD-induced steatosis.


Tuberous sclerosis complex-1 deficiency attenuates diet-induced hepatic lipid accumulation.

Kenerson HL, Yeh MM, Yeung RS - PLoS ONE (2011)

Histologic and biochemical effects of rapamycin on HFD-induced steatosis.A) Examples of histology (H&E) and Oil Red “O” staining of the livers procured from animals described in Figure 4. NCD, normal chow diet; HFD, high-fat diet; Rapa, rapamycin. Magnification, 400X. B) Western blots of representative liver lysates from each of the four groups shown in (A) highlighting the effects of chronic rapamycin on Akt(Ser473) phosphorylation. The average ratios of band intensities (Image J) between phospho- and total-Akt are summarized in the graph (n of 5 per group).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3066210&req=5

pone-0018075-g005: Histologic and biochemical effects of rapamycin on HFD-induced steatosis.A) Examples of histology (H&E) and Oil Red “O” staining of the livers procured from animals described in Figure 4. NCD, normal chow diet; HFD, high-fat diet; Rapa, rapamycin. Magnification, 400X. B) Western blots of representative liver lysates from each of the four groups shown in (A) highlighting the effects of chronic rapamycin on Akt(Ser473) phosphorylation. The average ratios of band intensities (Image J) between phospho- and total-Akt are summarized in the graph (n of 5 per group).
Mentions: Analysis of the livers revealed a significant increase in triglyceride levels in mice receiving HFD, and importantly, rapamycin did not alter hepatic TG levels significantly in either group of animals (Figure 4). This corroborates with the histologic findings of steatosis in the HFD-groups regardless of rapamycin treatment (Figure 5A). Further, rapamycin did not lead to any histologic change in the NCD-fed livers. Immunoblot analyses of the liver lysates showed a trend towards higher levels of Akt(Ser473) phosphorylation with HFD that were unchanged following two weeks of rapamycin (Figure 5B). Hence, despite evidence of worsening glucose intolerance, mTORC1 inhibition by rapamycin did not alter hepatic lipid content in a model of diet-induced steatosis. In contrast, the HFD-associated TG accumulation and insulin resistance reverted to baseline within 2 weeks of replacing the HFD with NCD. We conclude that mTORC1 is not necessary for the maintenance of HFD-induced steatosis.

Bottom Line: These observations suggest that mTORC1 is neither necessary nor sufficient for steatosis.Instead, Akt and mTORC1 have opposing effects on hepatic lipid accumulation such that mTORC1 protects against diet-induced steatosis.These findings provide novel insights into the role of mTORC1 in hepatic lipid metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is causally linked to type 2 diabetes, insulin resistance and dyslipidemia. In a normal liver, insulin suppresses gluconeogenesis and promotes lipogenesis. In type 2 diabetes, the liver exhibits selective insulin resistance by failing to inhibit hepatic glucose production while maintaining triglyceride synthesis. Evidence suggests that the insulin pathway bifurcates downstream of Akt to regulate these two processes. Specifically, mTORC1 has been implicated in lipogenesis, but its role on hepatic steatosis has not been examined. Here, we generated mice with hepatocyte-specific deletion of Tsc1 to study the effects of constitutive mTORC1 activation in the liver. These mice developed normally but displayed mild hepatomegaly and insulin resistance without obesity. Unexpectedly, the Tsc1- livers showed minimal signs of steatosis even under high-fat diet condition. This 'resistant' phenotype was reversed by rapamycin and could be overcome by the expression of Myr-Akt. Moreover, rapamycin failed to reduce hepatic triglyceride levels in models of steatosis secondary to Pten ablation in hepatocytes or high-fat diet in wild-type mice. These observations suggest that mTORC1 is neither necessary nor sufficient for steatosis. Instead, Akt and mTORC1 have opposing effects on hepatic lipid accumulation such that mTORC1 protects against diet-induced steatosis. Specifically, mTORC1 activity induces a metabolic shift towards fat utilization and glucose production in the liver. These findings provide novel insights into the role of mTORC1 in hepatic lipid metabolism.

Show MeSH
Related in: MedlinePlus