Gaucher disease (GD), an autosomal recessive disease, is characterized by accumulation of glucosylceramide mainly in cells of the reticuloendothelial system, due to mutations in the acid beta-glucocerebrosidase gene. Some of the patients suffer from neurological symptoms (type 2 and type 3 patients), whereas patients with type 1 GD do not present neurological signs. The disease is heterogeneous even among patients with the same genotype, implicating that a mutation in the glucocerebrosidase gene is required to cause GD but other factors play an important role in the manifestation of the disease. Glucocerebrosidase is a lysosomal enzyme, synthesized on endoplasmic reticulum (ER)-bound polyribosomes and translocated into the ER. Following N-linked glycosylations, it is transported to the Golgi apparatus, from where it is trafficked to the lysosomes. In this study, we tested glucocerebrosidase protein levels, N-glycans processing and intracellular localization in skin fibroblasts derived from patients with GD. Our results strongly suggest that mutant glucocerebrosidase variants present variable levels of ER retention and undergo ER-associated degradation in the proteasomes. The degree of ER retention and proteasomal degradation is one of the factors that determine GD severity.

The short-chain fatty acid propionate is a potent inhibitor of molds that is widely used as a food preservative and endogenously produced by gut microbiota. Although generally recognized as safe by the U.S. Food and Drug Administration, the metabolic effects of propionate consumption in humans are unclear. Here, we report that propionate stimulates glycogenolysis and hyperglycemia in mice by increasing plasma concentrations of glucagon and fatty acid–binding protein 4 (FABP4). Fabp4-deficient mice and mice lacking liver glucagon receptor were protected from the effects of propionate. Although propionate did not directly promote glucagon or FABP4 secretion in ex vivo rodent pancreatic islets and adipose tissue models, respectively, it activated the sympathetic nervous system in mice, leading to secretion of these hormones in vivo. This effect could be blocked by the pharmacological inhibition of norepinephrine, which prevented propionate-induced hyperglycemia in mice. In a randomized, double-blind, placebo-controlled study in humans, consumption of a propionate-containing mixed meal resulted in a postprandial increase in plasma glucagon, FABP4, and norepinephrine, leading to insulin resistance and compensatory hyperinsulinemia. Chronic exposure of mice to a propionate dose equivalent to that used for food preservation resulted in gradual weight gain. In humans, plasma propionate decreased with weight loss in the Dietary Intervention Randomized Controlled Trial (DIRECT) and served as an independent predictor of improved insulin sensitivity. Thus, propionate may activate a catecholamine-mediated increase in insulin counter-regulatory signals, leading to insulin resistance and hyperinsulinemia, which, over time, may promote adiposity and metabolic abnormalities. Further evaluation of the metabolic consequences of propionate consumption is warranted.

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Gaucher disease (GD), a sphingolipidosis characterized by impaired activity of the lysosomal enzyme glucocerebrosidase (GCase), results from mutations in the GCase-encoding gene, GBA. We have shown that mutant GCase variants present variable degrees of endoplasmic reticulum (ER) retention and undergo ER-associated degradation (ERAD) in the proteasome. Furthermore, the degree of ERAD of mutant GCase variants correlates with and is one of the factors that determine GD severity. An association between GD and Parkinson disease (PD) has been demonstrated by the concurrence of PD in GD patients and the identification of GCase mutations in probands with sporadic PD. One of the genes involved in PD is PARK2, encoding the E3 ubiquitin ligase parkin. Parkin functions in the ERAD of misfolded ER proteins, and it is upregulated by unfolded protein response. Loss of parkin function leads to the accumulation of its substrates, which is deleterious to dopaminergic neurons in PD. We, therefore, tested the possibility that the association between GD and PD reflects the fact that parkin acts as an E3 ligase of mutant GCase variants. Our results showed that mutant GCase variants associate with parkin. Normal parkin, but not its RING finger mutants, affects the stability of mutant GCase variants. Parkin also promotes the accumulation of mutant GCase in aggresome-like structures and is involved in K48-mediated polyubiquitination of GCase mutants, indicating its function as its E3 ligase. We suggest that involvement of parkin in the degradation of mutant GCase explains the concurrence of GD and PD.

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