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Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet.

Abstract

Low-carbohydrate diets are used to manage obesity, seizure disorders, and malignancies of the central nervous system. These diets create a distinctive, but incompletely defined, cellular, molecular, and integrated metabolic state. Here, we determine the systemic and hepatic effects of long-term administration of a very low-carbohydrate, low-protein, and high-fat ketogenic diet, serially comparing these effects to a high-simple-carbohydrate, high-fat Western diet and a low-fat, polysaccharide-rich control chow diet in C57BL/6J mice. Longitudinal measurement of body composition, serum metabolites, and intrahepatic fat content, using in vivo magnetic resonance spectroscopy, reveals that mice fed the ketogenic diet over 12 wk remain lean, euglycemic, and hypoinsulinemic but accumulate hepatic lipid in a temporal pattern very distinct from animals fed the Western diet. Ketogenic diet-fed mice ultimately develop systemic glucose intolerance, hepatic endoplasmic reticulum stress, steatosis, cellular injury, and macrophage accumulation, but surprisingly insulin-induced hepatic Akt phosphorylation and whole-body insulin responsiveness are not impaired. Moreover, whereas hepatic Pparg mRNA abundance is augmented by both high-fat diets, each diet confers splice variant specificity. The distinctive nutrient milieu created by long-term administration of this low-carbohydrate, low-protein ketogenic diet in mice evokes unique signatures of nonalcoholic fatty liver disease and whole-body glucose homeostasis.

Authors+Show Affiliations

Department of 1Medicine, Washington University, St. Louis, Missouri 63110, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21454445

Citation

Garbow, Joel R., et al. "Hepatic Steatosis, Inflammation, and ER Stress in Mice Maintained Long Term On a Very Low-carbohydrate Ketogenic Diet." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 300, no. 6, 2011, pp. G956-67.
Garbow JR, Doherty JM, Schugar RC, et al. Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. Am J Physiol Gastrointest Liver Physiol. 2011;300(6):G956-67.
Garbow, J. R., Doherty, J. M., Schugar, R. C., Travers, S., Weber, M. L., Wentz, A. E., ... Crawford, P. A. (2011). Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. American Journal of Physiology. Gastrointestinal and Liver Physiology, 300(6), pp. G956-67. doi:10.1152/ajpgi.00539.2010.
Garbow JR, et al. Hepatic Steatosis, Inflammation, and ER Stress in Mice Maintained Long Term On a Very Low-carbohydrate Ketogenic Diet. Am J Physiol Gastrointest Liver Physiol. 2011;300(6):G956-67. PubMed PMID: 21454445.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. AU - Garbow,Joel R, AU - Doherty,Jason M, AU - Schugar,Rebecca C, AU - Travers,Sarah, AU - Weber,Mary L, AU - Wentz,Anna E, AU - Ezenwajiaku,Nkiruka, AU - Cotter,David G, AU - Brunt,Elizabeth M, AU - Crawford,Peter A, Y1 - 2011/03/31/ PY - 2011/4/2/entrez PY - 2011/4/2/pubmed PY - 2011/8/19/medline SP - G956 EP - 67 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am. J. Physiol. Gastrointest. Liver Physiol. VL - 300 IS - 6 N2 - Low-carbohydrate diets are used to manage obesity, seizure disorders, and malignancies of the central nervous system. These diets create a distinctive, but incompletely defined, cellular, molecular, and integrated metabolic state. Here, we determine the systemic and hepatic effects of long-term administration of a very low-carbohydrate, low-protein, and high-fat ketogenic diet, serially comparing these effects to a high-simple-carbohydrate, high-fat Western diet and a low-fat, polysaccharide-rich control chow diet in C57BL/6J mice. Longitudinal measurement of body composition, serum metabolites, and intrahepatic fat content, using in vivo magnetic resonance spectroscopy, reveals that mice fed the ketogenic diet over 12 wk remain lean, euglycemic, and hypoinsulinemic but accumulate hepatic lipid in a temporal pattern very distinct from animals fed the Western diet. Ketogenic diet-fed mice ultimately develop systemic glucose intolerance, hepatic endoplasmic reticulum stress, steatosis, cellular injury, and macrophage accumulation, but surprisingly insulin-induced hepatic Akt phosphorylation and whole-body insulin responsiveness are not impaired. Moreover, whereas hepatic Pparg mRNA abundance is augmented by both high-fat diets, each diet confers splice variant specificity. The distinctive nutrient milieu created by long-term administration of this low-carbohydrate, low-protein ketogenic diet in mice evokes unique signatures of nonalcoholic fatty liver disease and whole-body glucose homeostasis. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/21454445/Hepatic_steatosis_inflammation_and_ER_stress_in_mice_maintained_long_term_on_a_very_low_carbohydrate_ketogenic_diet_ L2 - http://www.physiology.org/doi/full/10.1152/ajpgi.00539.2010?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -