Biology subjects

Zushin, P.-J. H.

Publications and source records attributed to Zushin, P.-J. H..

5 recordsLinked to original sources

bioRxiv2024

Viscoelastic high-molecular-weight hyaluronic acid hydrogels support rapid glioblastoma cell invasion with leader-follower dynamics

Hyaluronic acid (HA), the primary component of brain extracellular matrix, is increasingly used to model neuropathological processes, including glioblastoma (GBM) tumor invasion. While elastic hydrogels based on crosslinked low-molecular-weight (LMW) HA are widely exploited for this purpose and have proven valuable for discovery and screening, brain tissue is both viscoelastic and rich in high-MW (HMW) HA, and it remains unclear how these differences influence invasion. To address this question, hydrogels comprised of either HMW (1.5 MDa) or LMW (60 kDa) HA are introduced, characterized, and applied in GBM invasion studies. Unlike LMW HA hydrogels, HMW HA hydrogels relax stresses quickly, to a similar extent as brain tissue, and to a greater extent than many conventional HA-based scaffolds. GBM cells implanted within HMW HA hydrogels invade much more rapidly than in their LMW HA counterparts and exhibit distinct leader-follower dynamics. Leader cells adopt dendritic morphologies, similar to invasive GBM cells observed in vivo. Transcriptomic, pharmacologic, and imaging studies suggest that leader cells exploit hyaluronidase, an enzyme strongly enriched in human GBMs, to prime a path for followers. This study offers new insight into how HA viscoelastic properties drive invasion and argues for the use of highly stress-relaxing materials to model GBM.

bioengineering↗

bioRxiv2022

G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis

Human genetics has been instrumental in identification of genetic variants linked to type 2 diabetes (T2D). Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for T2D, but the mechanism behind this association has remained elusive. Here for the first time we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. Our findings establish a previously unknown role of Gpr151 in the liver and provides an explanation to the lowered T2D risk in individuals with nonsynonymous mutations in GPR151. This study highlights the therapeutic potential of targeting GPR151 for treatment of metabolic disease.

physiology↗

bioRxiv2022

Coenzyme Q regulates UCP1 expression and thermogenesis through the integrated stress responses

Coenzyme Q (CoQ) is an essential component of mitochondrial respiration1 and required for thermogenic activity in brown adipose tissues2 (BAT). CoQ deficiency leads to a wide range of pathological manifestations3 but mechanistic consequences of CoQ deficiency in specific tissues such as BAT remain poorly understood. Here we show that pharmacological or genetic CoQ deficiency (50-75% reduction) in BAT leads to accumulation of cytosolic mitochondrial RNAs (mtRNAs) and activation of the eIF2 kinase PKR resulting in the induction of the integrated stress response (ISR) and suppression of UCP1 expression in an ATF4-dependent fashion. Surprisingly, despite diminished UCP1 levels, BAT CoQ deficiency increases whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high fat diets (HFD). This mitohormesis like effect of BAT CoQ insufficiency is dependent on the ATF4-FGF21 axis in BAT revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.

cell biology↗

bioRxiv2020

4 β-hydroxycholesterol is a pro-lipogenic factor that promotes SREBP1c expression and activity through Liver X-receptor.

Oxysterols are oxidized derivatives of cholesterol that play signaling roles in lipid biosynthesis and homeostasis. Here we show that 4{beta}-hydroxycholesterol (4{beta}-HC), a liver and serum abundant oxysterol of poorly defined function, is a potent and selective inducer of the master lipogenic transcription factor, Sterol Regulatory Element Binding Protein 1c (SREBP1c), but not the related steroidogenic transcription factor SREBP2. Mechanistically, 4{beta}-HC acts as a putative agonist for Liver X receptor (LXR), a sterol sensor and transcriptional regulator previously linked to SREBP1c activation. Unique among the oxysterol agonists of LXR, 4{beta}-HC induced expression of the lipogenic program downstream of SREBP1c, and triggered de novo lipogenesis both in primary hepatocytes and in mouse liver. 4{beta}-HC-acted in parallel to insulin-PI3K-dependent signaling to stimulate triglyceride synthesis and lipid droplet accumulation. Thus, 4{beta}-HC is an endogenous regulator of de novo lipogenesis through the LXR-SREBP1c axis.

biochemistry↗

bioRxiv2020

Obesity-linked PPARγ S273 phosphorylation promotes insulin resistance through Growth Differentiation Factor 3

Overnutrition and obesity promote adipose tissue dysfunction, often leading to systemic insulin resistance. The thiazolidinediones (TZDs) are a potent class of insulin-sensitizing drugs and ligands of PPAR{gamma} that improve insulin sensitivity, but their use is limited due to significant side effects. Recently, we demonstrated a mechanism by which TZDs improve insulin sensitivity distinct from receptor agonism and adipogenesis: reversal of obesity-linked phosphorylation of PPAR{gamma} at Serine 273. However, the role of this modification has not been tested genetically. Here we demonstrate that mice encoding an allele of PPAR{gamma} which cannot be phosphorylated at S273 are protected from insulin resistance, without exhibiting differences in body weight or TZD-associated side effects. Indeed, hyperinsulinemic-euglycemic clamp experiments confirm improved insulin sensitivity, as evidenced by increased whole-body glucose uptake. RNA-seq experiments reveal PPAR{gamma} S273 phosphorylation specifically enhances transcription of Gdf3, a BMP family member. Ectopic expression of Gdf3 is sufficient to induce insulin resistance in lean, healthy mice. We find that Gdf3 can impact metabolism by inhibition of BMP signaling. Together, these results highlight the diabetogenic role of PPAR{gamma} S273 phosphorylation and focuses attention on a putative target, Gdf3.

cell biology↗