Central cellular signaling pathways involved with the regulation of lipid metabolism in the liver: a review

Abstract

The liver is primarily responsible for energy homeostasis and the regulation of lipid, carbohydrate and protein metabolism. Lipid metabolism consists of distributing lipids to peripheral tissues or ensuring their return to the liver to be reprocessed. Additionally, cellular metabolism is regulated by several molecules in different signaling pathways. Lipid homeostasis in the liver is mainly regulated by AKT, AMPK, SREBP, PPAR, and JNK. The PI3K/AKT/mTOR signaling pathway results in the biosynthesis of macromolecules and regulates lipogenesis and the expression of lipogenic genes. AMPK is an energy sensor that regulates metabolism and is activated when stored ATP is depleted, and it is responsible for the suppression of several key lipogenic factors in the liver related to cholesterol and fatty acid synthesis. SREBPs control lipogenic gene expression and cholesterol metabolism and act in the nutritional regulation of fatty acids and triglycerides. The continued activation of SREBPs is associated with cellular stress, inflammation and ultimately steatosis. PPARs are intrinsically important regulators of lipid metabolism. These genes are essential to various metabolic processes, especially lipid and glucose homeostasis, and can play a role in cell differentiation. JNK signaling is related to insulin resistance and its activation results in decreased mitochondrial activity and fat accumulation. Therefore, the study of cell signaling pathways related to lipid metabolism and liver function may help to identify abnormalities and develop strategies to manage and regulate metabolic disorders and resulting complications.

Luteolin loaded on zinc oxide nanoparticles ameliorates non-alcoholic fatty liver disease associated with insulin resistance in diabetic rats via regulation of PI3K/AKT/FoxO1 pathway

“…In this respect, our results showed a remarkable defect in the insulin signaling pathway manifested by the downregulated expression of IRS, PI3K, PDK1, and AKT with a concomitant upregulated expression of the nuclear FoxO1 which in turn activated the G6Pase a downstream target that promoted gluconeogenesis. These results agree with that of both Dwivedi et al 30 and Lopes et al 51 who reported that the status of insulin resistance is accompanied with the inhibition of the PI3K/AKT through FOXO1 activation promoting gluconeogenesis and thus hyperglycemia. Furthermore, Li et al 8 reported that the protein levels of PI3K and Akt in the liver of NAFLD were decreased while their activation would promote liver regeneration and suppress the progression of NAFLD.…”

Alterations of Central Liver Metabolism of Pediatric Patients with Non-Alcoholic Fatty Liver Disease

“…As first formulated in 1963 by Randle et al as a general principle, glucose and free fatty acids are competing substrates of cellular metabolism [ 29 ]. This antagonism is not limited to metabolic regulation at the enzyme level but is also realized in the activation of different groups of transcription factors and their associated signaling pathways [ 30 , 31 ]. Whereas steatosis and the resulting NASH are linked to elevated plasma levels of free fatty acids, IR and diabetes are linked to elevated plasma levels of glucose.…”