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J. Biol. Chem., Vol. 277, Issue 14, 11927-11932, April 5, 2002
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From the Department of Medical Bioscience, Umeå University,
S-901 87 Umeå, Sweden
During short term fasting, lipoprotein lipase
(LPL) activity in rat adipose tissue is rapidly down-regulated. This
down-regulation occurs on a posttranslational level; it is not
accompanied by changes in LPL mRNA or protein levels. The LPL
activity can be restored within 4 h by refeeding. Previously, we
showed that during fasting there is a shift in the distribution of
lipase protein toward an inactive form with low heparin affinity. To
study the nature of the regulatory mechanism, we determined the
in vivo turnover of LPL activity,
protein mass, and mRNA in rat adipose tissue. When protein
synthesis was inhibited with cycloheximide, LPL activity and protein
mass decreased rapidly and in parallel with half-lives of around 2 h, and the effect of refeeding was blocked. This indicates that
maintaining high levels of LPL activity requires continuous synthesis
of new enzyme protein. When transcription was inhibited by actinomycin,
LPL mRNA decreased with half-lives of 13.3 and 16.8 h in the
fed and fasted states, respectively, demonstrating slow turnover of the
LPL transcript. Surprisingly, when actinomycin was given to fed rats,
LPL activity was not down-regulated during fasting, indicating that
actinomycin interferes with the transcription of a gene that blocks the
activation of newly synthesized LPL protein. When actinomycin was given
to fasted rats, LPL activity increased 4-fold within 6 h, even in
the absence of refeeding. The same effect was seen with
Down-regulation of Adipose Tissue Lipoprotein Lipase during
Fasting Requires That a Gene, Separate from the Lipase Gene, Is
Switched On*
§,,
-amanitin,
another inhibitor of transcription. The response to actinomycin was
much less pronounced in aging rats, which are obese and
insulin-resistant. These data suggest a default state where LPL protein
is synthesized on a relatively stable mRNA and is processed into
its active form. During fasting, a gene is switched on whose product
prevents the enzyme from becoming active even though synthesis of LPL
protein continues unabated.
*
This study was funded by the Swedish Medical Research
Council Grant K98-03X-00727-33C.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally to this work.
§
Present address: Gladstone Institute of Cardiovascular Disease,
University of California, San Francisco, CA 94141-9100.
¶
To whom correspondence should be addressed. Tel.:
46-90-786-52-34; Fax: 46-90-786-78-40; E-mail:
Thomas.Olivecrona@medkem.umu.se.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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