Ketogenic essential amino acids modulate lipid synthetic pathways and prevent hepatic steatosis in mice.
BACKGROUND
Although dietary ketogenic essential amino acid (KAA) content modifies accumulation of hepatic lipids, the molecular interactions between KAAs and lipid metabolism are yet to be fully elucidated.


RESULTS
We designed a diet with a high ratio (E/N) of essential amino acids (EAAs) to non-EAAs by partially replacing dietary protein with 5 major free KAAs (Leu, Ile, Val, Lys and Thr) without altering carbohydrate and fat content. This high-KAA diet was assessed for its preventive effects on diet-induced hepatic steatosis and whole-animal insulin resistance. C57B6 mice were fed with a high-fat diet, and hyperinsulinemic ob/ob mice were fed with a high-fat or high-sucrose diet. The high-KAA diet improved hepatic steatosis with decreased de novo lipogenesis (DNL) fluxes as well as reduced expressions of lipogenic genes. In C57B6 mice, the high-KAA diet lowered postprandial insulin secretion and improved glucose tolerance, in association with restored expression of muscle insulin signaling proteins repressed by the high-fat diet. Lipotoxic metabolites and their synthetic fluxes were also evaluated with reference to insulin resistance. The high-KAA diet lowered muscle and liver ceramides, both by reducing dietary lipid incorporation into muscular ceramides and preventing incorporation of DNL-derived fatty acids into hepatic ceramides.


CONCLUSIONS
Our results indicate that dietary KAA intake improves hepatic steatosis and insulin resistance by modulating lipid synthetic pathways.
Noguchi
Yasushi
Y
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Nishikata
Natsumi
N
Shikata
Nahoko
N
Kimura
Yoshiko
Y
Aleman
Jose O
JO
Young
Jamey D
JD
Koyama
Naoto
N
Kelleher
Joanne K
JK
Takahashi
Michio
M
Stephanopoulos
Gregory
G
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D055423:Diet, Ketogenic; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D005527:Food, Fortified; D006946:Hyperinsulinism / Q000150:complications / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis* / Q000633:toxicity; D050155:Lipogenesis / Q000187:drug effects*; D008297:Male; D051379:Mice; D009765:Obesity / Q000150:complications / Q000209:etiology / Q000378:metabolism
D000596:Amino Acids; D008055:Lipids