Clusterin: full-length protein and one of its chains show opposing effects on cellular lipid accumulation

Abstract

Proteins, made up of either single or multiple chains, are designed to carry out specific biological functions. We found an interesting example of a two-chain protein where administration of one of its chains leads to a diametrically opposite outcome than that reported for the full-length protein. Clusterin is a highly glycosylated protein consisting of two chains, α- and β-clusterin. We have investigated the conformational features, cellular localization, lipid accumulation, in vivo effects and histological changes upon administration of recombinant individual chains of clusterin. We demonstrate that recombinant α- and β-chains exhibit structural and functional differences and differ in their sub-cellular localization. Full-length clusterin is known to lower lipid levels. In contrast, we find that β-chain-treated cells accumulate 2-fold more lipid than controls. Interestingly, α-chain-treated cells do not show such increase. Rabbits injected with β-chain, but not α-chain, show ~40% increase in weight, with adipocyte hypertrophy, liver and kidney steatosis. Many, sometimes contrasting, roles are ascribed to clusterin in obesity, metabolic syndrome and related conditions. Our findings of differential localization and activities of individual chains of clusterin should help in understanding better the roles of clusterin in metabolism.

Fibromodulin and regulation of the intricate balance between myoblast differentiation to myocytes or adipocyte‐like cells

“…In the present study, we found that Clu regulated myogenic marker genes during the differentiation stage in C2C12 cells. To examine its effect on lipid accumulation, we analyzed the expression of CD36 and PPARγ (well‐known lipid markers) and observed their diminished expression in Clu kd cells, which is in line with the lipid accumulating effect of Clu reported by Matukumalli et al (47). We examined lipid accumulation in FMOD wt and FMOD kd cells.…”

Could the glycosylation analysis of seminal plasma clusterin become a novel male infertility biomarker?

“…Matukumalli, Tangirala, and Rao (2017) proved that the properties of CLU differed depending on its subcellular localization. The authors documented that CLU composed of both (α and β) subunits lowered the lipid levels, whereas β‐chains caused intracellular lipid accumulation two times higher in comparison to the controls.…”

“…The α‐subunit did not present those features. Moreover, the weight of rabbits treated with β‐chains of CLU increased by 40% compared to the control, despite no change in the eating habits (Matukumalli et al, 2017).…”

Proteotranscriptomic Measurements of E6-Associated Protein (E6AP) Targets in DU145 Prostate Cancer Cells

“…Clusterin, a stress-induced chaperon protein (71), is involved in cell signaling (72), apoptosis (73), cellular migration (74), metastasis (75), DNA repair (76,77), lipid accumulation (78), and lipid transport (79). Clusterin was selected as a candidate to study further as it ranked as one of the top regulated candidates of E6AP and some of its functions are related to the biology of E6AP.…”