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

Joel R. Garbow, Jason M. Doherty, Rebecca C. Schugar, Sarah Travers, Mary L. Weber, Anna E. Wentz, Nkiruka Ezenwajiaku, David G. Cotter, Elizabeth M. Brunt, Peter A. Crawford

Research output: Contribution to journalArticlepeer-review

126 Scopus citations


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 longterm administration of a very low-carbohydrate, low-protein, and high-fat ketogenic diet, serially comparing these effects to a highsimple-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.

Original languageEnglish
Pages (from-to)G956-G967
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number6
StatePublished - Jun 2011


  • Fatty liver disease
  • High-fat diets
  • Insulin resistance
  • Magnetic resonance spectroscopy
  • Nutrient state
  • Peroxisome proliferators activated receptor-γ
  • Unfolded protein response
  • X-box-binding protein-1 splicing


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