Tissue-specific expression and dietary regulation of chimeric mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase/human growth hormone gene in transgenic mice

We have studied the role of the mitochondrial 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) synthase gene
in regulating ketogenesis. The gene exhibits expression
in various tissues and it is regulated in a tissue-specific
manner. To investigate the underlying mechanisms of
this expression, we linked a 1148-base-pair portion of
the mitochondrial HMG-CoA synthase promoter to the
human growth hormone (hGH) gene and analyzed the
expression of the hGH reporter gene in transgenic mice.
mRNA levels for hGH were observed in liver, testis,
ovary, stomach, colon, cecum, brown adipose tissue,
spleen, adrenal glands, and mammary glands from adult
mice, and also in liver and stomach, duodenum, jejunum, brown adipose tissue, and heart of suckling mice.
There was no expression either in kidney or in any other
nonketogenic tissue. The comparison between these
data and those of the endogenous mitochondrial HMGCoA synthase gene suggests that the 1148 base pairs of
the promoter contain the elements necessary for expression in liver and testis, but an enhancer is necessary for
full expression in intestine of suckling animals and that
a silencer prevents expression in stomach, brown adipose tissue, spleen, adrenal glands, and mammary
glands in wild type adult mice. In starvation, transgenic
mice showed higher expression in liver than did wild
type. Both refeeding and insulin injection reduced the
expression. Fat diets, composed in each case of different
fatty acids, produced similar expression levels, respectively, to those found in wild type animals, suggesting
that long-, medium-, and short-chain fatty acids may
exert a positive influence on the transcription rate in
this 1148-base-pair portion of the promoter. The ketogenic capacity of liver and the blood ketone body levels
were equal in transgenic mice and in nontransgenic
mice.