“New” hepatic fat activates PPARα to maintain glucose, lipid, and cholesterol homeostasis

Abstract

De novo lipogenesis is an energy-expensive process whose role in adult mammals is poorly understood. We generated mice with liver-specific inactivation of fatty-acid synthase (FAS), a key lipogenic enzyme. On a zero-fat diet, FASKOL (FAS knockout in liver) mice developed hypoglycemia and fatty liver, which were reversed with dietary fat. These phenotypes were also observed after prolonged fasting, similarly to fasted PPARalpha-deficiency mice. Hypoglycemia, fatty liver, and defects in expression of PPARalpha target genes in FASKOL mice were corrected with a PPARalpha agonist. On either zero-fat or chow diet, FASKOL mice had low serum and hepatic cholesterol levels with elevated SREBP-2, decreased HMG-CoA reductase expression, and decreased cholesterol biosynthesis; these were also corrected with a PPARalpha agonist. These results suggest that products of the FAS reaction regulate glucose, lipid, and cholesterol metabolism by serving as endogenous activators of distinct physiological pools of PPARalpha in adult liver.

IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity

“…However, in this case, there was a global increase (~2-to 13-fold) in the expression of PPARα target genes, such as Acox1, Hmgcs2, Cpt1a, Pdk4, Cyp4a10, Fgf21, Fabp1, and Acot1 (Fig. 3E), findings that are consistent with activation of PPARα by diet-derived fatty acids (23).…”

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

“…For this purpose, we applied conditional FASN KO mice 39 and various oncogene driven HCC mouse models, including AKT, AKT/c-Met and c-Met/ b-catenin models.…”

Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity

“…Also intracellular fatty acids derived from de novo lipogenesis or hydrolysis of triacylglycerol (TAG) or phospholipid can activate these transcription factors. For example, recent evidence suggests that modulating specific pathways, such as de novo fatty acid synthesis or TAG hydrolysis, which supply intracellular fatty acids, regulates gene expression (12,13). Such evidence that different regulation of these transcription factors by fatty acid type (unsaturated versus saturated) or source (intracellular versus exogenous) implicates that certain proteins or enzymes that control cellular uptake or trafficking of fatty acids and their downstream metabolites could mediate their effects on gene expression.…”