End-on versus parallel radiofrequency lesioning for neurotomy of the cervical medial branch nerves: a study protocol of a prospective, randomized, double-blind clinical trial: the "EndPaRL" study.

BACKGROUND: Cervical facet joint disease is a common source of neck pain and its prevalence increases with aging. Conservative multimodal management options (e.g., strengthening of neck muscles, non-steroidal anti-inflammatory medications, massage, and thermal modalities) often fail to relieve pain. Cervical medial branch nerve (CMBN) radiofrequency neurotomy (RFN) is an effective minimally invasive technique for treating chronic neck pain secondary to facet joint disease. An end-on approach for this procedure has been proposed that may be technically easier and require less time while reducing post-procedural discomfort. The protocol presented here is for a study that aims to compare the efficacy of a new end-on approach using multi-tined cannulae, against the conventional parallel technique that employs straight cannulae for RFN of the CMBN in patients with chronic neck pain due to cervical facet joint disease. METHODS: A multicentre randomized, non-inferior, active comparator-controlled trial will be conducted with two parallel groups and blinding of participants and outcome assessor. The study will include 72 adults with chronic neck pain secondary to facet joint disease who are candidates for RFA of the CMBN. Participants will be randomized to either the conventional parallel or the end-on approach in a 1:1 ratio. The intensity of pain and pain-related domains (function, quality of life, sleep, adverse effects of the interventions, analgesic intake) will be measured at 1, 3, 6, and 12 months after the procedure. DISCUSSION: Neck pain secondary to cervical facet joint disease is prevalent and RFA of the CMBN is a validated treatment for relieving it. The conventional parallel technique can be technically challenging, and it can be associated with adverse effects while the newer end-on approach has the potential of being a simpler technique with less adverse effects. This trial will be the first non-inferiority study to compare the clinical efficacy of the end-on approach against the conventional parallel approach for RFN of CMBN in patients with chronic neck pain due to cervical facet joint disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT05818774. Registered on April 20, 2023.

GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein.

BACKGROUND/OBJECTIVE: GLP-1R agonists have been shown to reduce fasting and postprandial plasma lipids, both of which are independent risk factors for the development of cardiovascular disease. However, how endogenous GLP-1 - which is rapidly degraded - modulates intestinal and hepatic lipid metabolism is less clear. A vagal gut-brain-axis originating in the portal vein has been proposed as a possible mechanism for GLP-1's anti-lipemic effects. Here we sought to examine the relationship between vagal GLP-1 signalling and intestinal lipid absorption and lipoprotein production. METHODS: Syrian golden hamsters or C57BL/6 mice received portal vein injections of GLP-1(7-36), and postprandial and fasting plasma TG, TRL TG, or VLDL TG were examined. These experiments were repeated during sympathetic blockade, and under a variety of pharmacological or surgical deafferentation techniques. In addition, hamsters received nodose ganglia injections of a GLP-1R agonist or antagonist to further probe the vagal pathway. Peripheral studies were repeated in a novel GLP-1R KO hamster model and in our diet-induced hamster models of insulin resistance. RESULTS: GLP-1(7-36) site-specifically reduced postprandial and fasting plasma lipids in both hamsters and mice. These inhibitory effects of GLP-1 were investigated via pharmacological and surgical denervation experiments and found to be dependent on intact afferent vagal signalling cascades and efferent changes in sympathetic tone. Furthermore, GLP-1R agonism in the nodose ganglia resulted in markedly reduced postprandial plasma TG and TRL TG, and fasting VLDL TG and this nodose GLP-1R activity was essential for portal GLP-1s effect. Notably, portal and nodose ganglia GLP-1 effects were lost in GLP-1R KO hamsters and following diet-induced insulin resistance. CONCLUSION: Our data demonstrates for the first time that portal GLP-1 modulates postprandial and fasting lipids via a complex vagal gut-brain-liver axis. Importantly, loss or interference with this signalling axis via surgical, pharmacological, or dietary intervention resulted in the loss of portal GLP-1s anti-lipemic effects. This supports emerging evidence that native GLP-1 works primarily through a vagal neuroendocrine mechanism.

miR-130b is a potent stimulator of hepatic very-low-density lipoprotein assembly and secretion via marked induction of microsomal triglyceride transfer protein.

miR-130b is a microRNA whose expression is particularly elevated within adipose tissue and in the circulation in diabetic states. Hepatic miR-130b expression has been linked to hepatocellular carcinoma and changes in lipid metabolism. Here, we investigated the role of miR-130b in hepatic lipid homeostasis and lipoprotein export. We observed that overexpression of miR-130b-3p or -5p in HepG2 cells markedly enhanced the secretion of very-low-density lipoprotein (VLDL) particles, enhanced the secretion of [3H]glycerol metabolically labeled triglyceride (TG), and significantly increased the number or the average size of lipid droplets (LDs), respectively. Overexpression of miR-130b also altered the expression of key genes involved in lipid metabolism and in particular markedly increased both mRNA and protein expression levels of microsomal triglyceride transfer protein (MTP). Conversely, the miR-130b inhibitor decreased mRNA levels of MTP and fatty acid synthase (FAS) in HepG2 cells. However, dual-luciferase reporter assays indicated that MTP is not a direct target of miR-130b-3p. miR-130b overexpression did not alter de novo synthesized TG or the stability and secretion of apolipoprotein B 100. Interestingly, knockdown of phosphatase and tensin homolog (PTEN) blocked the upregulation of MTP mRNA induced by miR-130b. Finally, miR-130b-induced stimulation of VLDL secretion was also observed in a second hepatocyte cell culture model, immortalized human hepatocytes, confirming the effects observed in HepG2 cells. Overall, these data suggest a potential role for miR-130b in promoting hepatic VLDL assembly and secretion mediated by marked stimulation of MTP expression and TG mobilization. Thus miR-130b overexpression corrects the defect in VLDL production in HepG2 cells.

Intestinal lipogenesis: how carbs turn on triglyceride production in the gut.

PURPOSE OF REVIEW: To review recent evidence for the role of carbohydrates in the promotion of de novo lipogenesis and lipoprotein secretion from the intestine. RECENT FINDINGS: The consumption of diets rich in carbohydrates have been shown to promote elevations in circulating lipids. In particular, the consumption of monosaccharides, such as glucose and fructose, have been shown to induce increases in intestinal de novo lipogenesis, as well as be used as a substrate for the synthesis of triglycerides and lipoprotein export in the form of chylomicrons. Recently, various systematic reviews have analyzed the relative contribution of dietary fructose to intestinal lipogenesis. Although, there remains controversy within the literature, the body of evidence supports lipogenic effects of high fructose diets. In addition, alterations in markers of de novo lipogenesis within the jejunum of patients with insulin resistance may explain the alterations in their postprandial lipid profile. SUMMARY: Recent evidence supports the contribution of dietary carbohydrates to intestinal lipogenesis and lipoprotein secretion; however, further research is required to fully understand the mechanisms underlying this complex process.

Gut peptide and neuroendocrine regulation of hepatic lipid and lipoprotein metabolism in health and disease.

Non-alcoholic fatty liver disease (NAFLD) is a continuum of disorders that can range from simple steatosis to non-alcoholic steatohepatitis (NASH). As a complex metabolic disorder, the pathophysiology of NAFLD is incompletely understood. Recently glucagon-like peptide (GLP)-1 and -2 signalling has been implicated in the pathogenesis of NAFLD. The role of these gut hormones in the hepatic abnormalities is complicated by lack of consensus on the presence of GLP-1 and GLP-2 receptors within the liver. Nevertheless, GLP-1 and GLP-2 receptor agonists have been associated with alterations in lipid metabolism and hepatic and systemic inflammation, pathological abnormalities characteristic of NAFLD. Treatment with GLP-1 analogues has been shown to reverse features of NAFLD including insulin resistance, and alterations in hepatic de novo lipogenesis and reactive oxygen species. In this review, we provide an overview of the role of GLP-1 and GLP-2 in lipid homeostasis and metabolic disease including NAFLD and NASH.

GLP-2 Dysregulates Hepatic Lipoprotein Metabolism, Inducing Fatty Liver and VLDL Overproduction in Male Hamsters and Mice.

Fundamental complications of insulin resistance and type 2 diabetes include the development of nonalcoholic fatty liver disease and an atherogenic fasting dyslipidemic profile, primarily due to increases in hepatic very-low-density lipoprotein (VLDL) production. Recently, central glucagon-like peptide-2 receptor (GLP2R) signaling has been implicated in regulating hepatic insulin sensitivity; however, its role in hepatic lipid and lipoprotein metabolism is unknown. We investigated the role of glucagon-like peptide-2 (GLP-2) in regulating hepatic lipid and lipoprotein metabolism in Syrian golden hamsters, C57BL/6J mice, and Glp2r-/- mice consuming either a normal chow or high-fat diet (HFD). In the chow-fed hamsters, IP GLP-2 administration significantly increased fasting dyslipidemia, hepatic VLDL production, and the expression of key genes involved in hepatic de novo lipogenesis. In HFD-fed hamsters and chow-fed mice, GLP-2 administration exacerbated or induced hepatic lipid accumulation. HFD-fed Glp2r-/- mice displayed reduced glucose tolerance, VLDL secretion, and microsomal transfer protein lipid transfer activity, as well as exacerbated fatty liver. Thus, we conclude that GLP-2 plays a lipogenic role in the liver by increasing lipogenic gene expression and inducing hepatic steatosis, fasting dyslipidemia, and VLDL overproduction. In contrast, the lack of Glp2r appears to interfere with VLDL secretion, resulting in enhanced hepatic lipid accumulation. These studies have uncovered a role for GLP-2 in maintaining hepatic lipid and lipoprotein homeostasis.