Effects of ChREBP deficiency on adrenal lipogenesis and steroidogenesis

Abstract

Carbohydrate response element binding protein (ChREBP) is critical in the regulation of fatty acid and triglyceride synthesis in the liver. Interestingly, Chrebp-/- mice show reduced levels of plasma cholesterol, which is critical for steroid hormone synthesis in adrenal glands. Furthermore, Chrebp mRNA expression was previously reported in human adrenal glands. Thus, it remains to be investigated whether ChREBP plays a role directly or indirectly in steroid hormone synthesis and release in adrenal glands. In the present study, we find that Chrebp mRNA is expressed in mouse adrenal glands and that ChREBP binds to carbohydrate response elements. Histological analysis of Chrebp-/- mice shows no adrenal hyperplasia and less oil red O staining compared with that in wild-type mice. In adrenal glands of Chrebp-/- mice, expression of Fasn and Scd1, two enzymes critical for fatty acid synthesis, was substantially lower and triglyceride content was reduced. Expression of Srebf2, a key transcription factor controlling synthesis and uptake of cholesterol and the target genes was upregulated, while cholesterol content was not significantly altered in the adrenal glands of Chrebp-/- mice. Adrenal corticosterone content and plasma adrenocorticotropic hormone and corticosterone levels were not significantly altered in Chrebp-/- mice. Consistently, expression of genes related to steroid hormone synthesis was not altered. Corticosterone secretion in response to two different stimuli, namely 24-h starvation and cosyntropin administration, were also not altered in Chrebp-/- mice. Taking these results together, corticosterone synthesis and release were not affected in Chrebp-/- mice despite reduced plasma cholesterol levels.

The Roles of Carbohydrate Response Element Binding Protein in the Relationship between Carbohydrate Intake and Diseases

“…ChREBP is a large protein (Mr = 94,600 Da) composed of 864 amino acids and belongs to the MONDO family of basic helix-loop-helix- and leucine zipper-type transcription factors [ 6 ]. ChREBP regulates lipogenic, glycolytic, fructolytic, gluconeogenic, and hormone/receptor pathways [ 8 , 9 , 10 , 52 , 57 , 58 ] and is expressed in the liver, intestine, muscle, white and brown adipose tissue, pancreatic islets, and adrenal glands [ 10 , 54 , 59 ]. ChREBP has two isoforms, ChREBP alpha and ChREBP beta [ 60 ].…”

“…ChREBP is moderately expressed in the adrenal glands [ 59 ]. Plasma cholesterol levels are also decreased in Chrebp -/- mice.…”

“…Moreover, cholesterol is converted into cortisone in adrenal glands. Chrebp -/- mice showed normal adrenal cholesterol and cortisol content but decreased triglyceride content [ 59 ]. Therefore, ChREBP may play a role in adrenal lipogenesis but not steroidogenesis [ 59 ].…”

New insights into the inter-organ crosstalk mediated by ChREBP

“…In addition to the regulation of glycolytic (liver pyruvate kinase (Lpk)) and lipogenic genes (fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scd1) and acetyl-CoA carboxylase 1 (Acc1) (7) more details below), ChREBP controls the expression of a vast number of genes which exert tissuespecific functions. ChREBP expression is mostly abundant in liver and white/brown adipose tissues (8) but it is also expressed in pancreatic islets (9), small intestine (8) and to a lesser extent in kidney (8), adrenal glands (10) and brain (8). ChREBP modulates pancreatic insulin production and secretion through its control of antioxidant/mitochondrial biogenic programs (nuclear factor erythroid 2-related factor 2 (Nrf2)), as well as pro-oxidative/apoptotic pathways (thioredoxin interacting protein (Txnip)) (11,12) and fructose absorption and metabolism (glucose transporter 2/5 (Glut2/5)), ketohexokinase (Khk), aldolase B (AldoB), triose phosphate isomerase (TrioK) and lactate dehydrogenase (Ldh) in the small intestine (13).…”

Network-based identification and prioritization of key transcriptional factors of diabetic kidney disease

“…It is a basic helix–loop–helix/leucine zipper TF produced in several metabolically related tissues, such as pancreatic β-cells, liver, and adipocytes, and acts as a moderator of glucose-responsive gene activation [36] , [37] , [38] . Following glucose stimulation, ChREBP translocates into the nucleus, thus producing a heterodimer with Max-like protein X (Mlx) that conjugate to the carbohydrate response element (ChRE) for transcriptional regulation of genes related to glucose, fatty acid steroid and lipid metabolism [38] , [39] , [40] , [41] , [42] .…”