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Abstract 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. Highlights • NAFLD (or fatty liver/steatosis) presents as a complex disorder, involving multiple metabolic dysfunctions. • Glucagon-like peptide-1(GLP) receptor agonists, such as exendin-4 and liraglutide, may be effective in combatting NAFLD. • GLP-1 based therapies decrease intrahepatic lipid accumulation and liver damage in patients suffering from NAFLD. • GLP-2 may also have anti-inflammatory effects in the liver however it may exacerbate hyperlipidemia and fatty liver. • Overall, GLP-1 and GLP-2 clearly play critical and diverse roles in metabolic regulation via a gut-brain-liver axis. [ABSTRACT FROM AUTHOR]

Introduction: A major complication of insulin resistant states is fasting dyslipidemia, a lipid profile characterized by elevated triglycerides, increased small dense LDL and low HDL-cholesterol. Recently, bile acid signaling has been suggested to improve hepatic insulin sensitivity and lipid accumulation through activation of the Takeda G protein-coupled receptor 5 (TGR5). Using CRISPR/CAS9 gene editing, and in collaboration with the Wang laboratory at Utah State University, we have developed a novel Tgr5-/- hamster model. As the role of TGR5 in regulating hepatic lipid and lipoprotein metabolism has not been explored, the present study was performed to characterize the fasting lipid profile of this model in normal and mild insulin resistant states and further examine bile acid signaling within these hamsters. Methods/Results: Eight-week-old Tgr5+/+ and Tgr5-/- hamsters were fed a high fat, high fructose and low cholesterol (FFLC) diet for 6 weeks. Glucose tolerance and fasting plasma lipids were examined at baseline, and following 6-weeks of FFLC consumption. Unlike the Tgr5+/+ hamsters, who exhibited impaired glucose tolerance following 6-weeks of FFLC-feeding, Tgr5-/- hamsters did not. This alteration in glucose tolerance was not associated with any significant differences in body weight or food consumption, or hepatic triglyceride or cholesterol between genotypes. Lipoprotein profiling was performed via FPLC analysis. Preliminary results suggest that Tgr5-/- hamsters exhibit reduced VLDL-triglyceride and -cholesterol, and HDL-cholesterol. Finally, chow fed hamsters received intraduodenal injections of deoxycholic acid (DCA), a bile acid with a strong affinity for TGR5. DCA administration was associated with reduced VLDL-triglyceride secretion in Tgr5+/+ hamsters, an effect that was blunted in Tgr5-/- hamsters. The present research will set a framework to expand our knowledge of the role of TGR5 signaling in hepatic lipogenesis. Disclosure: D.C.L. Alvares: None. S.S. Hoffman: None. K. Adeli: None. Funding: Heart and Stroke Foundation of Canada [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]