title: 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: Department of 1Medicine, Washington University, St. Louis, Missouri 63110, USA.
authors: Joel R
authors: JR
authors: Garbow
authors: Jason M
authors: JM
authors: Doherty
authors: Rebecca C
authors: RC
authors: Schugar
authors: Sarah
authors: S
authors: Travers
authors: Mary L
authors: ML
authors: Weber
authors: Anna E
authors: AE
authors: Wentz
authors: Nkiruka
authors: N
authors: Ezenwajiaku
authors: David G
authors: DG
authors: Cotter
authors: Elizabeth M
authors: EM
authors: Brunt
authors: Peter A
authors: PA
authors: Crawford
mesh_terms: D000704:Analysis of Variance; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D050528:Diet, Carbohydrate-Restricted / Q000009:adverse effects*; D055423:Diet, Ketogenic / Q000009:adverse effects*; D018753:Diet, Protein-Restricted; D004041:Dietary Fats / Q000008:administration & dosage / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D002149:Energy Intake; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000209:etiology / Q000378:metabolism; D007249:Inflammation / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D056811:Unfolded Protein Response
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D018836:Inflammation Mediators; D007328:Insulin; D047495:PPAR gamma; D014280:Triglycerides