Hepatic free fatty acids accumulate in experimental steatohepatitis: role of adaptive pathways.
OBJECTIVE
We determined the effects of dietary lipid composition on steatohepatitis development with particular attention to the nature of lipid molecules that accumulate in the liver and pathways of hepatic triglyceride synthesis.


METHODS
Mice were fed methionine and choline deficient (MCD) diets supplemented with 20% fat as lard (saturated) or olive oil (monounsaturated), for 3 weeks.


RESULTS
Irrespective of dietary lipid composition, MCD-fed mice developed steatosis, ballooning degeneration and lobular inflammation. MCD-feeding increased hepatic free fatty acid (FFA) levels 2-3-fold, as well as total triglyceride levels. Hepatic FFA composition was characterized by increased ratio of monounsaturated: saturated FFA. There were reduced nuclear levels of the lipogenic transcription factor sterol regulatory element binding protein-1 in MCD-fed mice, but no consistent reduction in fatty acid synthesis genes (acetyl-CoA carboxylase and fatty acid synthase). Consistent with pathways of hepatic triglyceride synthesis, expression of diacylglycerol acyltransferase-1 and -2 was increased, as were delta-5- and delta-6- fatty acid desaturase mRNA levels.


CONCLUSIONS
In this nutritional model of steatohepatitis, accumulation of FFA occurs despite substantial suppression of lipogenesis and induction of triglyceride synthesis genes. Accumulation of FFA supports a lipotoxicity mechanism for liver injury in this form of fatty liver disease.
Larter
Claire Z
CZ
Department of Gastroenterology and Hepatology, ANU Medical School, Australian National University at The Canberra Hospital, ACT, Australia.
Yeh
Matthew M
MM
Haigh
W Geoffrey
WG
Williams
Jacqueline
J
Brown
Sandie
S
Bell-Anderson
Kim S
KS
Lee
Sum P
SP
Farrell
Geoffrey C
GC
D000103:Acetyl-CoA Carboxylase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002849:Chromatography, Gas; D000090943:Delta-5 Fatty Acid Desaturase; D051048:Diacylglycerol O-Acyltransferase / Q000096:biosynthesis / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology; D004042:Dietary Fats, Unsaturated / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004591:Electrophoresis, Polyacrylamide Gel; D044943:Fatty Acid Desaturases / Q000096:biosynthesis / Q000235:genetics; D064429:Fatty Acid Synthases / Q000096:biosynthesis / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D050155:Lipogenesis / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D000069463:Olive Oil; D010938:Plant Oils / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis / Q000235:genetics
D000090943:Delta-5 Fatty Acid Desaturase; D004041:Dietary Fats; D004042:Dietary Fats, Unsaturated; D005230:Fatty Acids, Nonesterified; D000069463:Olive Oil; D010938:Plant Oils; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D044943:Fatty Acid Desaturases; D051048:Diacylglycerol O-Acyltransferase; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase; C029310:lard