A three-organelle complex made by wrappER contacts with peroxisome and mitochondria responds to liver lipid flux changes

Hepatic lipid homeostasis depends on intracellular pathways that respire fatty acid (FA) in peroxisomes and mitochondria and on systemic pathways that secrete FA into the bloodstream, either free or condensed in very-low-density lipoprotein (VLDL) triglycerides. These systemic and intracellular pathways are interdependent, but it is unclear whether and how they integrate into a single cellular circuit. Here, we report that mouse liver wrappER, a distinct ER compartment with apparent FA- and VLDL-secretion functions, connects peroxisomes and mitochondria. Correlative light electron microscopy, quantitative serial section electron tomography, and 3D organelle reconstruction analysis show that the number of peroxisome-wrappER-mitochondria complexes changes throughout fasting-to-feeding transitions and doubles when VLDL synthesis stops following acute genetic ablation of Mttp in the liver. Quantitative proteomic analysis of peroxisome-wrappER-mitochondria complex-enriched fractions indicates that the loss of Mttp upregulates global FA β-oxidation, thereby integrating the dynamics of this three-organelle association into hepatic FA flux responses. Therefore, liver lipid homeostasis occurs through the convergence of systemic and intracellular FA-elimination pathways in the peroxisome-wrappER-mitochondria complex.

The Role of Gut Microbiota and Its Produced Metabolites in Obesity, Dyslipidemia, Adipocyte Dysfunction, and Its Interventions

Obesity is becoming an increasing problem worldwide and is often, but not invariably, associated with dyslipidemia. The gut microbiota is increasingly linked to cardiovascular disease, nonalcoholic fatty liver disease, and type 2 diabetes mellitus. However, relatively little focus has been attributed to the role of gut-microbiota-derived metabolites in the development of dyslipidemia and alterations in lipid metabolism. In this review, we discuss current data involved in these processes and point out the therapeutic potentials. We cover the ability of gut microbiota metabolites to alter lipoprotein lipase action, VLDL secretion, and plasma triglyceride levels, and its effects on reverse cholesterol transport, adipocyte dysfunction, and adipose tissue inflammation. Finally, the current intervention strategies for treatment of obesity and dyslipidemia is addressed with emphasis on the role of gut microbiota metabolites and its ability to predict treatment efficacies.

LZP is required for hepatic triacylglycerol transportation through maintaining apolipoprotein B stability

The conserved zona pellucida (ZP) domain is found in hundreds of extracellular proteins that are expressed in various organs and play a variety of roles as structural components, receptors and tumor suppressors. A liver-specific zona pellucida domain-containing protein (LZP), also named OIT3, has been shown to be mainly expressed in human and mouse hepatocytes; however, the physiological function of LZP in the liver remains unclear. Here, we show that Lzp deletion inhibited very low-density lipoprotein (VLDL) secretion, leading to hepatic TG accumulation and lower serum TG levels in mice. The apolipoprotein B (apoB) levels were significantly decreased in the liver, serum, and VLDL particles of LZP-deficient mice. In the presence of LZP, which is localized to the endoplasmic reticulum (ER) and Golgi apparatus, the ER-associated degradation (ERAD) of apoB was attenuated; in contrast, in the absence of LZP, apoB was ubiquitinated by AMFR, a known E3 ubiquitin ligase specific for apoB, and was subsequently degraded, leading to lower hepatic apoB levels and inhibited VLDL secretion. Interestingly, hepatic LZP levels were elevated in mice challenged with a high-fat diet and humans with simple hepatic steatosis, suggesting that LZP contributes to the physiological regulation of hepatic TG homeostasis. In general, our data establish an essential role for LZP in hepatic TG transportation and VLDL secretion by preventing the AMFR-mediated ubiquitination and degradation of apoB and therefore provide insight into the molecular function of LZP in hepatic lipid metabolism.

Simultaneous inhibition of peripheral CB1R and iNOS mitigates obesity-related dyslipidemia through distinct mechanisms

Diabetic dyslipidemia (DD), characterized by increased plasma triglycerides (TGs) and decreased high-density lipoprotein cholesterol (HDL) levels, is a major factor contributing to non-alcoholic steatohepatitis (NASH) and cardiovascular risk in type-2 diabetes. Activation of both the cannabinoid-1 receptor (CB1R) and inducible nitric oxide synthase (iNOS) are associated with NASH progression. Here, we tested whether dual-targeting inhibition of hepatic CB1R and iNOS improves DD in diet-induced obese (DIO) mice. DIO mice were treated for 14 days with <i>(S)</i>-MRI-1867, a peripherally-restricted hybrid inhibitor of CB1R and iNOS. <a><i>(R)</i>-MRI-1867, the CB1R-inactive stereoisomer which retains iNOS inhibitory activity and JD-5037, a peripherally-restricted CB1R antagonist</a> were used to assess the relative contribution of the two targets to the effects of <i>(S)</i>-MRI-1867. <i>(S)</i>-MRI-1867 reduced hepatic steatosis, the rate of hepatic VLDL secretion, upregulated hepatic LDLR expression and reduced the circulating levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9). The decrease in VLDL secretion could be attributed to CB1R blockade while the reduction of PCSK9 levels and the related increase in LDLR resulted from iNOS inhibition via a mTORC1-dependent mechanism. In conclusion, this approach based on the concomitant inhibition of CB1R and iNOS represents a promising therapeutic strategy for the treatment of dyslipidemia.

Simultaneous inhibition of peripheral CB1R and iNOS mitigates obesity-related dyslipidemia through distinct mechanisms

Diabetic dyslipidemia (DD), characterized by increased plasma triglycerides (TGs) and decreased high-density lipoprotein cholesterol (HDL) levels, is a major factor contributing to non-alcoholic steatohepatitis (NASH) and cardiovascular risk in type-2 diabetes. Activation of both the cannabinoid-1 receptor (CB1R) and inducible nitric oxide synthase (iNOS) are associated with NASH progression. Here, we tested whether dual-targeting inhibition of hepatic CB1R and iNOS improves DD in diet-induced obese (DIO) mice. DIO mice were treated for 14 days with <i>(S)</i>-MRI-1867, a peripherally-restricted hybrid inhibitor of CB1R and iNOS. <a><i>(R)</i>-MRI-1867, the CB1R-inactive stereoisomer which retains iNOS inhibitory activity and JD-5037, a peripherally-restricted CB1R antagonist</a> were used to assess the relative contribution of the two targets to the effects of <i>(S)</i>-MRI-1867. <i>(S)</i>-MRI-1867 reduced hepatic steatosis, the rate of hepatic VLDL secretion, upregulated hepatic LDLR expression and reduced the circulating levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9). The decrease in VLDL secretion could be attributed to CB1R blockade while the reduction of PCSK9 levels and the related increase in LDLR resulted from iNOS inhibition via a mTORC1-dependent mechanism. In conclusion, this approach based on the concomitant inhibition of CB1R and iNOS represents a promising therapeutic strategy for the treatment of dyslipidemia.