Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression.
Nonalcoholic fatty liver disease (NAFLD) describes an increasingly prevalent spectrum of liver disorders associated with obesity and metabolic syndrome. It is uncertain why steatosis occurs in some individuals, whereas nonalcoholic steatohepatitis (NASH) occurs in others. We have generated a novel mouse model to test our hypothesis: that maternal fat intake contributes to the development of NAFLD in adult offspring. Female mice were fed either a high-fat (HF) or control chow (C) diet before and during gestation and lactation. Resulting offspring were fed either a C or a HF diet after weaning, to generate four offspring groups; HF/HF, HF/C, C/HF, C/C. At 15 weeks of age, liver histology was normal in both the C/C and HF/C offspring. Kleiner scoring showed that although the C/HF offspring developed nonalcoholic fatty liver, the HF/HF offspring developed NASH. At 30 weeks, histological analysis and Kleiner scoring showed that both the HF/C and C/HF groups had NAFLD, whereas the HF/HF had a more severe form of NASH. Therefore, exposure to a HF diet in utero and during lactation contributes toward NAFLD progression. We investigated the mechanisms by which this developmental priming is mediated. At 15 weeks of age, hepatic mitochondrial electron transport chain (ETC) enzyme complex activity (I, II/III, and IV) was reduced in both groups of offspring from HF-fed mothers (HF/C and HF/HF). In addition, measurement of hepatic gene expression indicated that lipogenesis, oxidative stress, and inflammatory pathways were up-regulated in the 15-week-old HF/C and HF/HF offspring.


CONCLUSIONS
Maternal fat intake contributes toward the NAFLD progression in adult offspring, which is mediated through impaired hepatic mitochondrial metabolism and up-regulated hepatic lipogenesis.
Bruce
Kimberley D
KD
Institute of Developmental Sciences, University of Southampton, Southampton General Hospital, Southampton, UK. kdb@soton.ac.uk
Cagampang
Felino R
FR
Argenton
Marco
M
Zhang
Junlong
J
Ethirajan
Priya L
PL
Burdge
Graham C
GC
Bateman
Adrian C
AC
Clough
Geraldine F
GF
Poston
Lucilla
L
Hanson
Mark A
MA
McConnell
Josie M
JM
Byrne
Christopher D
CD
D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004579:Electron Transport; D005234:Fatty Liver / Q000209:etiology*; D005260:Female; D005786:Gene Expression Regulation; D018960:Hyaluronan Receptors / Q000235:genetics; D050155:Lipogenesis; D039382:Maternal Nutritional Physiological Phenomena; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000378:metabolism*; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D011247:Pregnancy
D004041:Dietary Fats; D018960:Hyaluronan Receptors