Postprandial Hepatic Lipid Metabolism Requires Signaling Through Akt2 Independent of the Transcription Factors FoxA2, FoxO1, and SREBP1c

Cell Metab. 2011 Oct 5;14(4):516-27. doi: 10.1016/j.cmet.2011.09.001.

Abstract

Under conditions of obesity and insulin resistance, the serine/threonine protein kinase Akt/PKB is required for lipid accumulation in liver. Two forkhead transcription factors, FoxA2 and FoxO1, have been suggested to function downstream of and to be negatively regulated by Akt and are proposed as key determinants of hepatic triglyceride content. In this study, we utilize genetic loss of function experiments to show that constitutive activation of neither FoxA2 nor FoxO1 can account for the protection from steatosis afforded by deletion of Akt2 in liver. Rather, another downstream target positively regulated by Akt, the mTORC1 complex, is required in vivo for de novo lipogenesis and Srebp1c expression. Nonetheless, activation of mTORC1 and SREBP1c is not sufficient to drive postprandial lipogenesis in the absence of Akt2. These data show that insulin signaling through Akt2 promotes anabolic lipid metabolism independent of Foxa2 or FoxO1 and through pathways additional to the mTORC1-dependent activation of SREBP1c.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antirheumatic Agents / pharmacology
  • Aurothioglucose / pharmacology
  • Diet, High-Fat
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / deficiency
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Insulin / metabolism
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / physiology*
  • Liver / metabolism*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / deficiency
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction*
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism*
  • Triglycerides / metabolism

Substances

  • Antirheumatic Agents
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxa2 protein, mouse
  • Foxo1 protein, mouse
  • Insulin
  • Multiprotein Complexes
  • Proteins
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • Triglycerides
  • Hepatocyte Nuclear Factor 3-beta
  • Aurothioglucose
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt