Regulation of Genes for Enzymes Involved in Fatty Acid Synthesis^a

Abstract

The levels of malic enzyme and fatty acid synthase are increased by feeding and decreased by starvation in liver in vivo and are increased by triiodothyronine and decreased by glucagon in hepatocytes in culture. Cloned malic enzyme and fatty acid synthase cDNAs are being used to analyze regulation of these unique genes. Dietary regulation of both enzymes occurs at pretranslational steps. Increased transcription and increased mRNA stability contribute about equally to a 20-fold increase in malic enzyme mRNA level when starved ducklings are refed. In contrast, a 10-fold increase in the level of fatty acid synthase mRNA is largely accounted for by increased transcription of this gene. In chick-embryo hepatocytes incubated in serum-free medium containing insulin, triiodothyronine causes a greater than 10-fold increase in levels of both malic enzyme and fatty acid synthase mRNAs. Kinetic and inhibitor experiments suggest a protein intermediate in the increases of malic enzyme and fatty acid synthase mRNAs caused by triiodothyronine. For malic enzyme, the stimulation by triiodothyronine is predominantly posttranscriptional. Glucagon decreases the level of malic enzyme mRNA by 90 to 95%, with regulation occurring at a posttranscriptional step. Inhibitor experiments suggest that stimulation of the degradation of malic enzyme mRNA is partially responsible. Glucagon inhibited fatty acid synthase mRNA level by less than 50%; the inhibited step has not been identified. Thus, the coordinated regulation of malic enzyme and fatty acid synthase proteins by nutritional state may involve different hormones regulating at different points. A surprisingly large component of the regulation is posttranscriptional.

Abnormal Regulation of Hepatic Glucocorticoid Receptor mRNA and Receptor Protein Distribution in the Obese Zucker Rat

“…Due to the obvious differences in insulin levels between lean and obese Zuckers, the effect of insulin on the expression of specific hepatic genes has been questioned (4,5,15,46). Although insulin induces an increase in GAPDH mRNA in cultured adipocytes (2) and TAT and ME (17) in hepatocytes, no such effect has been observed for GR. Therefore, it is unlikely that insulin is directly responsible for the altered levels of GR mRNA in the fa/fa rat.…”

HORMONE-DEPENDENT AND HORMONE-INDEPENDENT CONTROL OF METABOLIC AND DE­VEL­OP­MEN­TAL FUNCTIONS OF MALATE DEHYDROGENASE – Review

“…It is well known that in mammalian and avian models, thyroid hormone (ORTIZ- CARO and JOLIN 1991;MOORADIAN et al, 1991;SALATI et al, 1991;MANN et al, 1992) and some steroids like estradiol (AS- TIAZARAN et al, 1989;PATNAIK, 1990), androsterone MOHAN and CLEARY, 1991) and nandrolone (TYLICKI et al, 2007) may stimulate activity of MDH by increasing MDH gene transcription and stabilizing MDH mRNA (SONG et al, 1988;DESVERGNE et al, 1991). Thyroidal control of malate dehydrogenase, specifically cytosolic malic enzyme, activity and function is well documented phenomenon in higher vertebrates (FRENKEL 1975;GOODRIDGE 1975;BAGCHI et al, 1986;GOODRIDGE et al, 1986GOODRIDGE et al, , 1989GOODRIDGE et al, , 1991GOODRIDGE et al, , 1996NIKO-DEM et al, 1989;IRITANI 1992). Moreover, rat MDH is positively regulated by both thyroid hormones and retinoids via their nuclear receptors recognizing specific response elements upstream of MDH promoter (MORI-OKA et al, 1989;PETTY et al, 1990).…”

SREBP-1 integrates the actions of thyroid hormone, insulin, cAMP, and medium-chain fatty acids on ACCα transcription in hepatocytes

“…For example, in livers of starved chickens, the rate of ACC ␣ transcription is low; consumption of a high-carbohydrate, low-fat diet stimulates an 11-fold increase in ACC ␣ transcription (22). The induction of ACC ␣ transcription caused by dietary carbohydrate is preceded or paralleled by increases in the molar ratio of insulin/glucagon and the level of T3 in the blood (23). In primary cultures of chick embryo hepatocytes (CEHs), addition of T3 to the culture medium stimulates a 7-fold increase in ACC ␣ transcription (24).…”