Abstract
SLC35B4, solute receptor for UDP-N-acetylglucosamine and UDP-xylose, is associated with diabetes and predisposing conditions. This study investigated the localization of SLC35B4 and compared the differential expression between a knockdown of SLC35B4 and controls in HepG2. Responsiveness to glucose, expression, and localization were assayed using Western blot and immunostaining. Localization was confirmed using a proximity ligation assay. Two-dimensional (2D) gel electrophoresis and MALDI-TOF were used to identify differentially expressed proteins and pathway analysis was performed. SLC35B4 was increased by 60% upon glucose stimulation and localized in Golgi apparatus and endoplasmic reticulum. Presence of SLC35B4 in the Golgi apparatus suggests its involvement in the biosynthesis of glycoconjugate proteins. Four proteins were markedly under-expressed (Hsp60, HspA8, TUBA1A, and ENO1) and linked to the pathogenesis of diabetes or post-translationally modified by O-GlcNAc. Glucose levels activate SLC35B4 expression. This triggers a downstream effect via Hsp60 and other proteins. We hypothesize that the downstream effect on the proteins is mediated via altering the glycosylation pattern inside liver cells. The downstream cascade ultimately alters the ability of cultured liver cells to inhibit endogenous glucose production, and this could play a role in the association of the above-listed genes with the pathogenesis of diabetes.
Highlights
Diabetes is one of the most common endocrine disorders worldwide, imposing tremendous health and economic burdens [1]
The findings of this study investigated the downstream effect of SLC35B4 and its ability to respond to glucose
In the present study, based on the downstream proteomics analysis in human liver cells and the localization assessment of the receptor and the response to glucose, the results obtained demonstrated that the expression of SLC35B4 is abundant in primary liver cells and can be altered by glucose in a dose-dependent manner in liver cell cultures
Summary
Diabetes is one of the most common endocrine disorders worldwide, imposing tremendous health and economic burdens [1]. In 2014, worldwide diabetes health expenditure ranged between. Out of all diabetes cases, Type II diabetes (T2D) accounts for around. The resulting hyperglycemia is currently controlled by lifestyle modifications or medications, such as sulfonylureas or metformin, which dramatically reduce morbidity. These therapies frequently fail to achieve optimal glycemic levels, which is important to minimize the risk of microvascular and other complications [6]. There is overwhelming evidence in the literature that susceptibility to T2D is highly heritable, ranging from 20 to 80% [7]. The cumulative contribution of the identified genetic variants accounts for only
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