Oxysterol Binding Protein Induces Upregulation of SREBP-1c and Enhances Hepatic Lipogenesis

Abstract

Background-Oxysterol binding protein (OSBP) has previously been implicated as a sterol sensor that regulates sphingomyelin synthesis and the activity of extracellular signal-regulated kinases (ERK). Methods and Results-We determined the effects of adenovirus-mediated hepatic overexpression of OSBP and its homologues ORP1L and ORP3 on mouse serum lipids. Whereas ORP1L and ORP3 had no effect on serum lipids, OSBP induced a marked increase of VLDL triglycerides (TG). Also, the liver tissue TG were elevated in the AdOSBP-injected mice, and their TG secretion rate was increased by 70%. The messenger RNAs for enzymes of fatty acid synthesis and their transcriptional regulator, SREBP-1c, as well as the Insig-1 mRNA, were upregulated two-fold in the OSBPexpressing livers. No change occurred in the messages of liver X receptor target genes ABCA1, ABCG5, and CYP7A1, and the Insig-2a mRNA was reduced. The phosphorylation of ERK was decreased in AdOSBP-infected liver and cultured hepatocytes. Importantly, silencing of OSBP in hepatocytes suppressed the induction of SREBP1-c by insulin and resulted in a reduction of TG synthesis. T he liver plays a central role in triglyceride (TG) and cholesterol homeostasis. Complex regulatory circuits within hepatocytes maintain the body lipid homeostasis under varying environmental conditions. Hepatic lipid syntheses and fluxes are controlled by transcription factors that respond to signals from a variety of lipidous ligands. The synthesis of cholesterol and fatty acids as well as the uptake of cholesterol and hepatic glucose use are controlled by sterol regulatory element binding proteins, SREBP. 1,2 A two-step proteolytic cleavage of SREBP precursors occurs within the Golgi complex and releases a basic helix-loop-helix-leucine zipper (bHLH-LZ) transcription factor denoted nuclear SREBP (nSREBP). The cleavage is controlled by the endoplasmic reticulum (ER) cholesterol content, which is sensed by SREBP cleavage activating protein (SCAP). SCAP, together with Insig proteins, retains SREBP within the ER when cholesterol is abundant but escorts it to the Golgi complex on cholesterol depletion. In addition to cholesterol, exogenously added oxysterol 25-hydroxycholesterol (25OH) is a potent inducer of SREBP activation, suggesting that also endogenous cellular oxysterols regulate the SREBP machinery. 2 Of the 3 SREBPs, SREBP-1c is particularly abundant in the liver where its expression is regulated by insulin and glucagon, and it plays a major role in controlling hepatic lipogenesis and glucose use. 1,3 SREBP-2, also expressed at relatively high levels in the liver, is responsible for control of cholesterol metabolism. The third family member, SREBP-1a, functions in both cholesterol and TG metabolism. In cultured cells, SREBP-1a is expressed at much higher levels than SREBP1c. 4 The cleavage of SREBP-1a and -2 precursors is regulated by cholesterol status, whereas the expression and maturation of SREBP-1c are primarily regulated by nutritional factors. SREBP-1c expression in liver, white adipos...

Osthole improves glucose and lipid metabolism via modulation of PPARα/γ-mediated target gene expression in liver, adipose tissue, and skeletal muscle in fatty liver rats

“…The activation of SREBP-1c can cause hepatic lipogenic gene transcription and hepatosteatosis (Jump et al 2005). Increase in the expression of FAS may increase fatty acid synthesis and lead to the ectopic over-accumulation of fatty acids and TG in liver (Yan et al 2007) and the IR (Boden et al 2005). It is known that activated PPARa/g can suppress the expression of SREBP-1, and decrease the synthesis of fatty acids and TG (Konig et al 2009).…”

Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism

“…Alternatively, oxysterols can bind to the oxysterol binding protein (OSBP)-related proteins (32). OSBP-related proteins constitute a family of cytosolic proteins involved in lipid metabolism (33). Interestingly, recent studies have shown that OSBPs can inhibit the catalytic activity of PP2A phosphatases that are involved in the control of the phosphorylation of Akt (34).…”

Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing

“…Although several members of the OSBP/ORP family have been putatively associated with some diseases, [37][38][39] the implication in hearing impairment had not been previously reported, and little was known about the relationship between OSBP/ORPs (including other lipid transport proteins) and the cell physiology of the inner ear. Laitinen et al 20 proved that OSBPL2 was expressed in almost all human tissues, but the inner ear or cochlea was not included in that work, and almost nothing was known about the role of OSBPL2 in the human ear.…”