Channy Park

Excessive lipid accumulation impairs digestion and gastrointestinal function. Transmembrane protein 135 (TMEM135) is involved in lipid metabolism of various tissues. Here, TMEM135 deficiency increased intestinal lipid absorption through ELOVL6-dependent oleoylethanolamide production and subsequent activation of peroxisome proliferator-activated receptor alpha (PPARα), which upregulated CD36 at the plasma membrane in the intestine of mice fed a high-fat diet or lard oil. Despite this enhanced lipid uptake, long-term lipid accumulation was suppressed by elevated peroxisomal and mitochondrial β-oxidation through increased fatty acid oxidation and oxidative phosphorylation activities without chylomicron secretion in TMEM135-depleted intestine. Inhibition of PPARα or ELOVL6 attenuated these effects. Furthermore, consistent results were observed in both TMEM135 KO and intestine-specific TMEM135 ^iKO mice, confirming tissue-specific rather than systemic effects. Overall, these results provide insight into the role of TMEM135 as a regulatory node connecting intestinal lipid absorption and systemic energy expenditure, contributing to the coordination between lipid storage and oxidation during metabolic adaptation.

Background: The kidney is an organ rich in peroxisomes, which play a pivotal role in fatty acid oxidation and ROS decomposition. Importantly, peroxisomal dysfunction contributes to the development and progression of various renal diseases. Therefore, we aimed to elucidate whether peroxisomes affect renal damage and fibrosis over time using a unilateral ureteral obstruction (UUO) mouse model. Methods: Expression levels of peroxisome-related factors and ROS- and hypoxia-related genes in UUO mice were measured in a time-dependent manner. Results: UUO led to renal damage and fibrosis progression over time; it significantly increased the protein expression levels of ATG5 and ATG7, while it decreased PMP70 and PEX14 protein expression. In particular, UUO increased the protein expression level of pexophagy receptor NBR1. Although the number of peroxisomes decreased, the protein expression levels of peroxisomal biogenesis-related proteins such as PEX11b, PEX16, and PEX19 remained constant. Decreased lipid metabolism due to reductions in ACOX1, DBP, and catalase caused by UUO and increased ROS production through peroxisomal degradation and mitochondrial antioxidant enzyme dysfunction were observed. Additionally, HIF-1α protein levels gradually increased in the UUO mice, whereas those of HIF-2α initially increased and then decreased. Conclusions: UUO is characterized by a progressive, chronological reduction in peroxisomal markers. Our findings indicate that peroxisomal degradation and associated metabolic dysfunction are tightly correlated with the progression of kidney injury and fibrosis, suggesting a potential involvement of compromised peroxisomal homeostasis in renal pathogenesis rather than proving a direct causal mechanism. Maintaining peroxisomal quality control may nevertheless represent a potential therapeutic avenue for chronic kidney disease.

Solute carrier family 25 (SLC25) is known to facilitate the transport of diverse metabolites across the mitochondrial and peroxisomal membranes. SLC25A17 is the only member of the SLC25 protein localized to peroxisomes; formerly known as PMP34, it also shares conserved sequence features with other SLC families. SLC25A17 was first described as an ATP transporter, but conflicting results regarding cofactor specificity in various experimental models obscure its precise function. Similarly, phenotypic differences between experimental models, such as mice and zebrafish, complicate the application of animal studies to humans. In particular, SLC25A17 deficiency is associated with peroxisomal dysfunction, and SLC25A17 expression is affected in various cancers and bipolar disorder, while the underlying molecular mechanisms remain unknown. Furthermore, it remains unclear whether altered SLC25A17 expression is a cause or consequence of human disease. This review provides an overview on current knowledge of SLC25A17, focusing on its known functions and emerging roles in human diseases. This may also help future studies in understanding its metabolic significance and disease pathogenesis.

The breakdown of Golgi proteins disrupts lipid trafficking, leading to lipid accumulation in the small intestine. However, the causal mechanism of the effects of Golgi protein degradation on the Golgi structure related to lipid trafficking in the small intestine remains unknown. Here we find that Golgi protein degradation occurs under hypoxic conditions in high-fat-diet-fed mice. Hypoxia-induced degradation promotes structural changes in the Golgi apparatus, termed ‘Golgi condensation’. In addition, hypoxia-inducible factor 1α (HIF-1α) activation enhances Golgi condensation through the ubiquitination and degradation of Golgi matrix protein 130 (GM130), which is facilitated by neural precursor cell expressed developmentally downregulated protein 4 (NEDD4). Golgi condensation upon exposure to hypoxia promotes lipid accumulation, apolipoprotein A1 retention and decreased chylomicron secretion in the intestinal epithelium. Golgi condensation and lipid accumulation induced by GM130 depletion are reversed by exogenous GM130 induction in the intestinal epithelium. Inhibition of either HIF-1α or NEDD4 protects against GM130 degradation and, thereby, rescues cells from Golgi condensation, which further increases apolipoprotein A1 secretion and lipid accumulation both in vivo and in vitro. Furthermore, the HIF-1α inhibitor PX-478 prevents Golgi condensation, which decreases lipid accumulation and promotes high-density lipoprotein secretion in high-fat-diet-fed mice. Overall, our results suggest that Golgi condensation plays a key role in lipid trafficking in the small intestine through the HIF-1α- and NEDD4-mediated degradation of GM130, and these findings highlight the possibility that the prevention of structural modifications in the Golgi apparatus can ameliorate intestinal lipid accumulation in obese individuals.

Peroxisomes generate reactive oxygen species (ROS) and also play a role in protecting cells from the damaging effects of such radicals. Dysfunctional peroxisomes are recognized by receptors and degraded by a selective type of macroautophagy called pexophagy. Oxidative stress is one of the signals that activates pexophagy through multiple signaling pathways. Conversely, impaired pexophagy results in the accumulation of damaged peroxisomes, which in turn leads to elevated ROS levels and oxidative stress, resulting as cellular dysfunction and the progression of diseases such as neurodegeneration, cancer, and metabolic disorders. This review explores the molecular mechanisms driving pexophagy and its regulation by oxidative stress with a particular focus on ROS. This highlights the role of peroxisomal proteins and ROS-mediated signaling pathways in regulating pexophagy. In addition, emerging evidence suggests that the dysregulation of pexophagy is closely linked to neurological disorders, underscoring its potential as a therapeutic target. Understanding the intricate crosstalk between pexophagy and oxidative stress provides new insights into the maintenance of cellular homeostasis and offers promising directions for addressing neurological disorders that are tightly associated with pexophagy and oxidative stress.

Background: Autophagy is an intracellular degradation process crucial for homeostasis. During autophagy, a double-membrane autophagosome fuses with lysosome through SNARE machinery STX17 to form autolysosome for degradation of damaged organelle. Whereas defective autophagy enhances cholesterol accumulation in the lysosome and impaired autophagic flux that results Niemann-Pick type C1 (NPC1) disease. However, exact interconnection between NPC1 and autophagic flux remain obscure due to the existence of controversial reports.Results: This study aimed at a comparison of the effects of three autophagic inhibitor drugs, including chloroquine, U18666A, and bafilomycin A1, on the intracellular cholesterol transport and autophagy flux. Chloroquine, an autophagic flux inhibitor; U1866A, a NPC1 inhibitor, and bafilomycin A, a lysosomotropic agent are well known to inhibit autophagy by different mechanism. Here we showed that treatment with U1866A and bafilomycin A induces lysosomal cholesterol accumulation that prevented autophagic flux by decreasing autophagosome–lysosome fusion. We also demonstrated that accumulation of cholesterol within the lysosome did not affect lysosomal pH. Although the clearance of accumulated cholesterol by cyclodextrin restored the defective autophagosome–lysosome fusion, the autophagy flux restoration was possible only when lysosomal acidification was not altered. In addition, a failure of STX17 trafficking to autophagosomes plays a key role in prevention of autophagy flux caused by intracellular cholesterol transport inhibitors.Conclusions: Our data provide a new insight that the impaired autophagy flux does not necessarily result in lysosomal cholesterol accumulation even though it prevents autophagosome–lysosome fusion.

Peroxisomes are dynamic organelles that participate in a diverse array of cellular processes, including β‐oxidation, which produces a considerable amount of reactive oxygen species (ROS). Although we showed that catalase depletion induces ROS‐mediated pexophagy in cells, the effect of catalase deficiency during conditions that favor ROS generation remains elusive in mice. In this study, we reported that prolonged fasting in catalase‐knockout (KO) mice drastically increased ROS production, which induced liver‐specific pexophagy, an autophagic degradation of peroxisomes. In addition, increased ROS generation induced the production of pro‐inflammatory cytokines in the liver tissues of catalase‐KO mice. Furthermore, there was a significant increase in the levels of aspartate transaminase and alanine transaminase as well as apparent cell death in the liver of catalase‐KO mice during prolonged fasting. However, an intra‐peritoneal injection of the antioxidant N‐acetyl‐l‐cysteine (NAC) and autophagy inhibitor chloroquine inhibited the inflammatory response, liver damage, and pexophagy in the liver of catalase‐KO mice during prolonged fasting. Consistently, genetic ablation of autophagy, Atg5 led to suppression of pexophagy during catalase inhibition by 3‐aminotriazole (3AT). Moreover, treatment with chloroquine also ameliorated the inflammatory response and cell death in embryonic fibroblast cells from catalase‐KO mice. Taken together, our data suggest that ROS‐mediated liver‐specific pexophagy observed during prolonged fasting in catalase‐KO mice may be responsible for the process associated with hepatic cell death.