Perk Is Dispensable for Smooth Muscle Cell Phenotype Switching in Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology · 2026-05-14

BACKGROUND: Smooth muscle cell (SMC) derived cells form the bulk of cells in atherosclerotic lesions and modulate lesion stability and cardiovascular disease outcomes. Unfolded protein response (UPR) markers, thin fibrous caps, and inflammation correlate with human lesion instability and rupture. In mice, UPR drives macrophage and endothelial apoptosis and inflammation, but its impact on lesion stability through SMC modulation is debated. The UPR protein Perk (protein kinase RNA-like ER kinase) was recently shown to drive SMC modulation in vivo, suggesting that depletion of SMC Perk may regulate lesion stability. METHODS: hypercholesterolemic mice. Lesions were scored for features of lesion stability and analyzed for differential expression at the single-cell level. Perk knockdown in primary murine SMCs was used to study Perk's effect on SMC modulation in vitro. UPR marker expression in human carotid lesions was assessed for UPR markers through scRNA-seq, bulk RNA-seq, and Xenium spatial transcriptomics. RESULTS: SMC Perk deletion in adult atherogenic mice did not affect weight gain or serum cholesterol levels. Lesions from Perk knockout mice resembled Perk WT counterparts with similar progression, lesion stability features, and cell populations. Scoring of UPR activity and differential expression analysis found little UPR activity in SMC and smooth muscle-derived cell populations. Perk was not required for in vitro SMC modulation in atherogenic conditions. No correlation was found between UPR markers and lesion stability or symptomatic clinical presentation in human carotid lesions, and UPR markers were expressed primarily in infiltrating leukocytes rather than in SMCs and stromal cells. CONCLUSIONS: SMC Perk UPR does not play a significant role in atherosclerotic SMC modulation, disease progression, or features of lesion stability in mice. Similarly, expression of markers of the Perk UPR pathway in humans does not correlate with human carotid lesion stability or clinical presentation.

Unraveling the physiological impact of ANGPTL8 loss-of-function variants in humans

Scientific Reports · 2026-04-29

Angiopoietin-like 8 (ANGPTL8) is a calorically responsive regulator of lipoprotein lipase (LPL). It does this by forming complexes with ANGPTL3 or ANGPTL4 that either inhibit LPL in oxidative tissues or preserve LPL activity in adipose tissue, respectively. Human heterozygous (reference allele/alternate allele, R/A) carriers of rs145464906/p.Q121X and rs760351239/p.Q131X ANGPTL8 protein truncating variants (PTVs) have favorable lipid profiles and decreased cardiovascular risk. Given the purported role of ANGPTL8 in redirecting circulating lipids in response to feeding, it is not clear why these PTVs should profile as they do. We elucidated this process by investigating these ANGPTL8 PTVs along with several novel ANGPTL8 putative loss of function (pLOF) variants, including a splice donor variant rs774984872/c.459 + 1G > T that was predicted to result in an ANGPTL8 truncation (p.K165X), in a consanguineous population from the Pakistan Genomic Resource (PGR). We observed lower TG, lower total cholesterol, and increased HDL-C in heterozygous carriers of these variants, consistent with previous reports for p.Q121X and p.Q131X and confirmed decreased ANGPTL3/8 and ANGPTL4/8 complex levels in serum samples from these carriers compared to non-carriers (R/R). Biochemically, the p.Q121X, p.Q131X and c.459 + 1G > T mutations showed dramatically reduced ANGPTL3/8 complex-mediated LPL inhibition while only modestly decreasing ANGPTL4/8-mediated preservation of LPL activity. Furthermore, a cohort of 14 participants that included 8 non-carriers, 5 heterozygous carriers and a single homozygous (A/A) individual of the c.459 + 1G > T pLOF variant were recruited for kinetic studies following standard mixed meal tolerance tests. Heterozygous carriers showed significantly reduced postprandial TG excursions compared to non-carriers. Together, these results support the concept that pLOF variants in ANGPTL8 result in favorable lipid profiles by selectively reducing ANGPTL3/8-mediated LPL inhibition while largely maintaining ANGPTL4/8-mediated preservation of LPL activity.

A non-apoptotic caspase-8–meteorin pathway in hepatocytes promotes MASH fibrosis

Nature Metabolism · 2025-09-26 · 3 citations

Metabolic-dysfunction-associated steatohepatitis (MASH) is the leading cause of chronic liver disease, but an incomplete understanding of MASH-induced liver fibrosis has limited therapeutic options. Here we show that hepatocyte caspase-8 drives MASH fibrosis through an apoptosis-independent mechanism. Hepatic caspase-8 expression correlates with liver fibrosis in both human and experimental MASH, and hepatocyte-specific caspase-8 deletion in male mice with MASH suppressed liver fibrosis and hepatic stellate cell (HSC) activation without affecting hepatocyte apoptosis. Mechanistic studies showed that a caspase-8-YY1 pathway in hepatocytes induces secretory meteorin (Metrn), which activates HSCs via a c-Kit-STAT3 pathway. Meteorin expression was increased in human and male mouse MASH livers and decreased by deletion of hepatocyte caspase-8 in MASH mice and human and mouse primary hepatocytes. Genetic restoration of hepatocyte meteorin in hepatocyte-caspase-8-deleted MASH mice restored HSC activation and liver fibrosis while silencing hepatocyte meteorin lowered liver fibrosis. These findings reveal a therapeutically targetable pathway promoting MASH fibrosis involving a non-apoptotic function of caspase-8 and a newly discovered HSC activator, meteorin.

The effect of LRRK2 loss-of-function variants in humans

UNC Libraries · 2025-05-14

Identification of genetic effects underlying type 2 diabetes in South Asian and European populations

UNC Libraries · 2025-04-16

Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification

UNC Libraries · 2025-10-01

Cross-species studies implicate the melanocortin 3 receptor more strongly in the control of pubertal development than energy balance

Molecular Metabolism · 2025-12-11 · 1 citations

. We detected a canine MC3R missense variant (p.M320I) which is common in labrador retrievers and showed that this significantly impairs receptor signalling. Dogs homozygous for p.M320I were lighter and showed delayed pubertal development but were not significantly more obese than wild-type or heterozygous dogs. We also established that the lack of Mc3r delayed pubertal development in both male and female mice. Finally, we studied growth and pubertal trajectories of individuals carrying rare loss-of-function MC3R variants and found that male carriers had delayed peak weight velocity and genital development but had no evidence for excess body fat compared to non-carriers. Our results support MC3R having a conserved role across mammals in controlling growth and pubertal timing. While MC3R deficiency may influence linear growth and body composition, complete loss of MC3R does not result in a penetrant human obesity syndrome.

Author Correction: The effect of LRRK2 loss-of-function variants in humans

UNC Libraries · 2025-05-14

Human CD33 deficiency is associated with mild alteration of circulating white blood cell counts

PLoS Genetics · 2025-03-05 · 3 citations

The single pass transmembrane protein CD33 is enriched in phagocytic and hematopoietic cell types, such as monocytes. CD33 is thought to be associated with immune cell function, susceptibility to Alzheimer's disease, and rare leukemias. Antagonism or genetic ablation of CD33 has been proposed to treat Alzheimer's disease, hematological cancers, and as a selection mechanism for enriching genetically altered blood cells. To understand the impact of chronic CD33 loss or ablation, we describe individuals who we confirmed to be missing CD33 due to germline loss of function variants. Through PheWAS-based approaches using existing whole exome biobanks and bespoke phenotyping using recall-by-genotype (RBG) studies, we show that CD33 loss of function alters circulating white blood cell counts and distributions, albeit mildly and with no overt clinical pathology. These findings indicate that chronic CD33 antagonism/ablation is likely to be safe in humans.

Caspase 1–deficient humans survive into late adulthood despite dramatically lower canonical inflammasome activity

Journal of Allergy and Clinical Immunology · 2025-10-15 · 1 citations