Biology subjects

Zeigerer, A.

Publications and source records attributed to Zeigerer, A..

3 recordsLinked to original sources

bioRxiv2021

Hepatocyte-specific activity of TSC22D4 triggers progressive NAFLD by impairing mitochondrial function

ObjectiveFibrotic organ responses have recently been identified as long-term complication in diabetes. Indeed, insulin resistance and aberrant hepatic lipid accumulation represent driving features of progressive non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis and non-alcoholic steatohepatitis (NASH) to fibrosis. Effective pharmacological regimens to stop progressive liver disease are still lacking to-date. MethodsBased on our previous discovery of transforming growth factor beta-like stimulated clone (TSC)22D4 as a key driver of insulin resistance and glucose intolerance in obesity and type 2 diabetes, we generated a TSC22D4-hepatocyte specific knockout line (TSC22D4-HepaKO) and exposed mice to control or NASH diet models. Mechanistic insights were generated by metabolic phenotyping and single cell liver sequencing. ResultsHepatic TSC22D4 expression was significantly correlated with markers of liver disease progression and fibrosis in both murine and human livers. Indeed, hepatic TSC22D4 levels were elevated in human NASH patients as well as in several murine NASH models. Specific genetic deletion of TSC22D4 in hepatocytes led to reduced liver lipid accumulation, improvements in steatosis and inflammation scores and decreased apoptosis in mice. Single cell RNA sequencing revealed a distinct gene signature identifying an upregulation of mitochondrial-related processes. An enrichment of genes involved in the TCA cycle, mitochondrial organization, and triglyceride metabolism underscored the hepatocyte-protective phenotype and overall decreased liver damage as seen in mouse models. ConclusionsTogether, our data uncover a new connection between targeted depletion of TSC22D4 and intrinsic metabolic processes in progressive liver disease. Cell-specific reduction of TSC22D4 improves hepatic steatosis, inflammation and promotes hepatocyte survival thus paving the way for further preclinical therapy developments.

physiology↗

bioRxiv2021

The obesity-linked human lncRNA AATBC regulates adipocyte plasticity by stimulating mitochondrial dynamics and respiration

Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, the activation of thermogenic brown and beige adipocytes is linked to improved cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this adipocyte plasticity could help improving energy balance and weight loss. Here, we show that the long non-coding RNA (lncRNA) Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Searching for new human lncRNAs implicated in adipocyte biology we compared transcriptional profiles of human adipose tissues and cultured adipocytes and discovered that AATBC was enriched in thermogenic conditions. Using primary human adipocytes and immortalized human adipocytes we found that gain-of-function of AATBC enhanced the thermogenic phenotype whereas loss-of-function diminished this effect. The AATBC-mediated increase in mitochondrial respiration was linked to a more fragmented mitochondrial network and vice versa. While we found that AATBC is predominantly located in the nucleus, its effect on global transcription was only marginal. As AATBC is specific to humans, we expressed AATBC in adipose tissue of mice to study its systemic impact, which led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, body mass index and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans.

molecular biology↗

bioRxiv2021

Transcriptomic analysis reveals niche gene expression effects of beta-hydroxybutyrate in primary myotubes

Various forms of fasting, including time-restricted feeding, alternate day fasting, and periodic fasting have shown promise in clinical and pre-clinical studies to normalize body weight, improve metabolic health, and protect against disease. Recent studies suggest that {beta}-hydroxybutyrate ({beta}OHB), a characteristic ketone body of the fasted metabolic state, acts as a potential signaling molecule mediating the beneficial effects of the various forms of fasting, potentially by acting as a histone deacetylase inhibitor. In the first part we investigated whether {beta}OHB, in comparison to the well-established histone deacetylase inhibitor butyrate, influences cellular differentiation in vitro. In C2C12 myotubes, 3T3-L1 adipocytes, and THP-1 monocytes, millimolar concentrations of {beta}OHB did not alter differentiation, as determined by gene expression and histological assessment, whereas equimolar concentrations of butyrate potently impaired differentiation in all cell types. RNA-sequencing revealed that unlike butyrate, {beta}OHB minimally impacted gene expression in adipocytes, macrophages, and hepatocytes. However, in myocytes, {beta}OHB upregulated genes involved in the TCA cycle and oxidative phosphorylation, while downregulating genes belonging to cytokine and chemokine signal transduction. Overall, our data do not support the notion that {beta}OHB serves as a powerful signaling molecule regulating gene expression in adipocytes, macrophages and hepatocytes, but suggest that {beta}OHB may act as a niche signaling molecule in muscle.

molecular biology↗