Biology subjects

Hellerstein, M.

Publications and source records attributed to Hellerstein, M..

7 recordsLinked to original sources

bioRxiv2025

Nutrient-Sensing Nuclear Receptor PPARα Controls Liver Proteostasis

Peroxisome proliferator-activated receptor alpha (PPAR) is a nuclear receptor that orchestrates metabolic adaptation to fasting by regulating hepatic lipid and glucose metabolism. While these functions are well established, its role in protein homeostasis, another energy-intensive process, has remained unclear. Here, we performed multi-omics analyses in wild-type and PPAR knockout mice treated with the PPAR agonist fenofibrate to define its broader role in proteostasis. Interestingly, chronic PPAR activation suppressed hepatic secretory pathways, reducing secretome gene expression and circulating serum proteins, and downregulated genes involved in endoplasmic reticulum (ER) translocation, glycosylation, folding, and trafficking. Concurrently, PPAR activation enhanced proteasome activity, which was associated with selective induction of proteasome 26S subunit non-ATPase (PSMD) family members. In addition, hepatic protein synthesis was strongly attenuated. This was associated with an increase in the inhibitory phosphorylation of the eukaryotic translation initiation factor 2 (eIF2), that in turn was linked to disrupted iron homeostasis. Together, these findings identify PPAR as a regulator of proteostasis, suppressing protein synthesis and secretion while promoting protein degradation pathways. Beyond its canonical role in lipid and glucose metabolism, we conclude that PPAR exerts an additional energy-conserving function by coordinating proteostasis, expanding our understanding of its systemic metabolic role.

physiology↗

bioRxiv2023

Adipocyte lipin 1 is positively associated with metabolic health in humans and regulates systemic metabolism in mice.

Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol (DAG), the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared to lean subjects and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multi-omic phenotyping demonstrated that adipocyte-specific Lpin1-/- mice had a metabolically-unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of nonalcoholic steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health and its loss predisposes mice to nonalcoholic steatohepatitis.

physiology↗

bioRxiv2021

Increased remodeling and impaired adaption to endurance exercise in desminopathy

Desminopathy the most common intermediate filament disease in humans. Desmin is an essential part of the filamentous network that aligns myofibrils, anchors nuclei and mitochondria, and connects the z-discs and the sarcolemma. We created a rat model with a mutation in R349P DES, analog to the most frequent R350P DES missense mutation in humans. To examine the effects of a chronic, physiological exercise stimulus on desminopathic muscle, we subjected R349P DES rats and their wildtype (WT) and heterozygous littermates to a treadmill running regime. We saw significantly lower running capacity in DES rats that worsened over the course of the study. We found indicators of increased autophagic and proteasome activity with running in DES compared to WT. Stable isotope labeling and LC-MS analysis displayed distinct adaptations of the proteomes of WT and DES animals at baseline as well as with exercise: While key proteins of glycolysis, mitochondria and thick filaments increased their synthetic activity with running in WT, these proteins were higher at baseline in DES and did not change with running. The results suggest an impairment in adaption to chronic exercise in DES muscle and a subsequent exacerbation in the functional and histopathological phenotype.

physiology↗

bioRxiv2021

Aging alters the metabolic flux signature of the ER unfolded protein response in vivo in mice

Age is a risk factor for numerous diseases, including neurodegenerative diseases, cancers, and diabetes. Loss of protein homeostasis is a central hallmark of aging. Activation of the endoplasmic reticulum unfolded protein response (UPRER) includes changes in protein translation and membrane lipid synthesis. Using stable isotope labeling, a "signature" of the UPRER in vivo in mouse liver was developed by inducing ER stress and measuring rates of both proteome-wide translation and de novo lipogenesis. Several changes in protein synthesis across ontologies were noted with age, including a more dramatic suppression of translation under ER stress in aged mice as compared to young mice. Binding immunoglobulin protein (BiP) synthesis rates and mRNA levels were increased more in aged than young mice. De novo lipogenesis rates decreased under ER stress conditions in aged mice, including both triglyceride and phospholipid fractions. In young mice, only a significant reduction was seen in the triglyceride fraction. These data indicate that aged mice have an exaggerated response to ER stress, which may indicate that the aging renders the UPRER less effective in resolving proteotoxic stress.

physiology↗

bioRxiv2021

Dynamics and turnover of memory CD8 T cell responses following yellow fever vaccination

Understanding how immunological memory lasts a lifetime requires quantifying changes in the number of memory cells as well as how their division and death rates change over time. We address these questions by using a statistically powerful mixed-effects differential equations framework to analyze data from two human studies that follow CD8 T cell responses to the yellow fever vaccine (YFV-17D). Models were first fit to the frequency and division rates of YFV-specific memory CD8 T cells 42 days to 1 year post-vaccination. A different dataset, on the loss of YFV-specific CD8 T cells over three decades, was used to assess out of sample predictions of our models. The commonly used exponential and bi-exponential decline models performed relatively poorly. Models with the cell loss following a power law (exactly or approximately) were most predictive. Notably, using only the first year of data, these models accurately predicted T cell frequencies up to 30 years post-vaccination. Our analyses suggest that division rates of these cells drop and plateau at a low level (0.001 per day, ~double estimates for naive T cells) within one year following vaccination, whereas death rates continue to decline for much longer. Our results show that power laws can be predictive for T cell memory, a finding that may be useful for vaccine evaluation and epidemiological modeling. Moreover, since power laws asymptotically decline more slowly than any exponential decline, our results help explain the longevity of immune memory phenomenologically. Author summaryImmunological memory, generated in response to infection or vaccination, may provide complete or partial protection from antigenically similar infections for the lifetime. Memory CD8 T cells are important players in protection from secondary viral infections but quantitative understanding of their dynamics in humans is limited. We analyze data from two studies where immunization with the yellow fever virus vaccine (YFV-17D) generates a mild acute infection and long-term memory. We find that: (i) the division rate of YFV-17D-specific CD8 T cells drops and stabilizes at ~ 0.1% per day during the first year following vaccination whereas the death rate declines more gradually, and (ii) the number of these cells declines approximately in accordance with a power law ({propto}time-0.82) for at least several decades following vaccination.

immunology↗

bioRxiv2020

A Novel SARS-CoV-2 Multitope Protein/Peptide Vaccine Candidate is Highly Immunogenic and Prevents Lung Infection in an Adeno Associated Virus Human Angiotensin-Converting Enzyme 2 (AAV hACE2) Mouse Model

A novel multitope protein-peptide vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and disease is described in this report. The initial development and characterization experiments are presented along with proof-of-concept studies for the vaccine candidate UB-612. UB-612 consists of eight components rationally designed for induction of potently neutralizing antibodies and broad T cell responses against SARS-CoV-2: the S1-RBD-sFc fusion protein, six synthetic peptides (one universal peptide and five SARS-CoV-2-derived peptides), a proprietary CpG TLR-9 agonist at low concentration as an excipient, and aluminum phosphate adjuvant. Through immunogenicity studies in Guinea pigs and rats, we optimized the design of protein/peptide immunogens and selected an adjuvant system, yielding a vaccine that provides excellent S1-RBD binding and high neutralizing antibody responses, robust cellular responses, and a Th1-oriented response at low doses. In challenge studies, UB- 612 vaccination reduced viral load and prevented development of disease in mouse and non-human primate challenge models. With a Phase 1 trial completed, a Phase 2 trial ongoing in Taiwan, and additional trials planned to support global authorizations, UB-612 is a highly promising and differentiated vaccine candidate for prevention of SARS-CoV-2 infection and COVID-19 disease. Author SummarySARS-CoV-2 virus, the causative agent of Coronavirus Disease 2019 (COVID-19), has spread globally since its origin in 2019, causing an unprecedented public health crisis that has resulted in greater than 4.7 million deaths worldwide. Many vaccines are under development to limit disease spread and reduce the number of cases, but additional candidates that promote a robust immune response are needed. Here, we describe a multitope protein-peptide vaccine platform that is unique among COVID-19 vaccines. The advantages of our approach are induction of both high levels of neutralizing antibodies as well as a Th/CTL response in the vaccinated host, which mimics the immune response that occurs after natural infection with SARS-CoV-2. We demonstrate that our vaccine is immunogenic and effective in preventing disease in several animal models, including AAV- hACE-2 transduced mice, and both rhesus and cynomolgus macaques. Importantly, no immunopathology was observed in the lungs of immunized animals, therefore showing that antibody-dependent enhancement (ADE) does not occur. Our study provides an additional, novel vaccine candidate for advancement in clinical trials to treat and prevent SARS-CoV-2 infection and COVID-19 disease.

immunology↗

bioRxiv2020

Cytoskeletal tension forces mitohormesis

Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programmed cell death. The biochemical milieu is known to affect mitochondrial function and contribute to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of ageing. However, the physical characteristics of the extracellular matrix are also altered in cancer and in aging tissues. We demonstrate that cells sense the physical properties of the extracellular matrix and activate a mitochondrial stress response that adaptively tunes mitochondrial function via SLC9A1-dependent ion exchange and HSF1-dependent transcription. Overall, our data indicate that adhesion-mediated mechanosignaling may play an unappreciated role in the altered mitochondrial functions observed in aging and cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/979583v3_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1ecdaceorg.highwire.dtl.DTLVardef@1112c32org.highwire.dtl.DTLVardef@6c99a1org.highwire.dtl.DTLVardef@1da1e5f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗