DHCR24 inhibitor SH42 increases desmosterol without preventing atherosclerosis development in mice.

The liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol, a final intermediate in cholesterol biosynthesis, has been identified as a selective LXR ligand that suppresses inflammation without inducing lipogenesis. Δ24-Dehydrocholesterol reductase (DHCR24) converts desmosterol into cholesterol, and we previously showed that the DHCR24 inhibitor SH42 increases desmosterol to activate LXR and attenuate experimental peritonitis and metabolic dysfunction-associated steatotic liver disease. Here, we aimed to evaluate the effect of SH42 on atherosclerosis development in APOE∗3-Leiden.CETP mice and low-density lipoproteins (LDL) receptor knockout mice, models for lipid- and inflammation-driven atherosclerosis, respectively. In both models, SH42 increased desmosterol without affecting plasma lipids. While reducing liver lipids in APOE∗3-Leiden.CETP mice, and regulating populations of circulating monocytes in LDL receptor knockout mice, SH42 did not attenuate atherosclerosis in either model.

Combined GIP receptor and GLP1 receptor agonism attenuates NAFLD in male APOE∗3-Leiden.CETP mice.

BACKGROUND: Combined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism is superior to single GLP1R agonism with respect to glycemic control and weight loss in obese patients with or without type 2 diabetes. As insulin resistance and obesity are strong risk factors for nonalcoholic fatty liver disease (NAFLD), in the current study we investigated the effects of combined GIPR/GLP1R agonism on NAFLD development. METHODS: Male APOE∗3-Leiden.CETP mice, a humanized model for diabetic dyslipidemia and NAFLD when fed a high-fat high-cholesterol diet, received subcutaneous injections with either vehicle, a GIPR agonist, a GLP1R agonist, or both agonists combined every other day. FINDINGS: GIPR and GLP1R agonism reduced body weight and additively lowered fasting plasma levels of glucose, triglycerides and total cholesterol. Strikingly, we report an additive reduction in hepatic steatosis as evidenced by lower hepatic lipid content and NAFLD scores. Underlying the lipid-lowering effects were a reduced food intake and intestinal lipid absorption and an increased uptake of glucose and triglyceride-derived fatty acids by energy-combusting brown adipose tissue. Combined GIPR/GLP1R agonism also attenuated hepatic inflammation as evidenced by a decreased number of monocyte-derived Kupffer cells and a reduced expression of inflammatory markers. Together, the reduced hepatic steatosis and inflammation coincided with lowered markers of liver injury. INTERPRETATION: We interpretate that GIPR and GLP1R agonism additively attenuate hepatic steatosis, lower hepatic inflammation, ameliorate liver injury, together preventing NAFLD development in humanized APOE∗3-Leiden.CETP mice. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to attenuate NAFLD progression in humans. FUNDING: This work was supported by a grant from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences [CVON-GENIUS-II] to P.C.N.R., a Lilly Research Award Program [LRAP] Award to P.C.N.R. and S.K., a Dutch Heart Foundation [2017T016] grant to S.K., and an NWO-VENI grant [09150161910073] to M.R.B.; J.F.D.B. is supported by the Nutrition and Health initiative of the University of Groningen; Z.Y. is supported by a full-time PhD scholarship from the China Scholarship Council (201806850094 to Z.Y.).

Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation.

Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24-dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti-inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3-Leiden. CETP mice, a well-established translational model that develops diet-induced human-like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet-induced hepatic steatosis and inflammation in a strictly LXRα-dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH.

Effects of dietary methionine restriction on postnatal growth, insulin sensitivity, and glucose metabolism in intrauterine growth retardation pigs at 49 and 105 d of age.

This study was conducted to investigate the effects of methionine restriction (MR) on growth performance, insulin sensitivity, and hepatic and muscle glucose metabolism in intrauterine growth retardation (IUGR) pigs at 49 and 105 d of age. At weaning (day 21), 30 female normal birth weight (NBW) piglets were fed control diets with adequate methionine (NBW-CON), whereas 60 female IUGR piglets were fed either the control diets (IUGR-CON) or MR diets which were 30% reduced in methionine (IUGR-MR) (n = 6 replicates (pens) with five piglets per replicate). At 49 and 105 d of age, one pig with a BW near to the mean of each replication was selected for biochemical analysis. Compared with NBW-CON pigs, IUGR-CON pigs exhibited lower relative daily gain (RDG) and homeostasis model assessment of insulin resistance (HOMA-IR) index at day 49 (P < 0.05), but higher RDG and HOMA-IR index at day 105 (P < 0.05). Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (G6Pase) activities were higher in IUGR-CON than NBW-CON pigs at both days 49 and 105 (P < 0.05), while hepatic glycogen synthase and glycogen phosphorylase activities were lower in IUGR-CON pigs at both two ages (P < 0.05). In addition, compared with NBW-CON pigs, IUGR-CON pigs (105-d old) had lower protein kinase B phosphorylation (PKB/Akt) in liver (P < 0.05), but not in muscle (P > 0.05). Compared with IUGR-CON pigs, IUGR-MR pigs had lower RDG at day 49, less blood glucose at day 105, and lower HOMA-IR index at both days 49 and 105 (P < 0.05). Additionally, compared with IUGR-CON pigs, MR decreased IUGR-MR pigs' hepatic G6Pase activities and increased their hepatic glycogen contents at day 105 (P < 0.05), as well as increased their hepatic and muscle PKB/Akt phosphorylation (P < 0.05). In conclusion, the ability of dietary MR to restrict IUGR pigs' growth and to reduce blood glucose appeared, respectively, in earlier and later period, but MR improved IUGR pigs' insulin sensitivity at both days 49 and 105.

Effects of dimethylglycine sodium salt supplementation on growth performance, hepatic antioxidant capacity, and mitochondria-related gene expression in weanling piglets born with low birth weight1.

Dimethylglycine sodium salt (DMG-Na) has exhibited excellent advantages in animal experiments and human health. The present study aimed to investigate the effects of dietary supplementation with 0.1% DMG-Na on the growth performance, hepatic antioxidant capacity, and mRNA expression of mitochondria-related genes in low birth weight (LBW) piglets during weaning period. Sixteen piglets with normal birth weight (NBW) and 16 LBW piglets were fed either a basal diet or a 0.1% DMG-Na supplemented diet from age of 21 to 49 d. Blood and liver samples were collected at the end of the study. The results showed that compared with NBW piglets, LBW piglets exhibited greater (P < 0.05) alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase activities in the serum. LBW decreased (P < 0.05) the activity of glutathione peroxidase and increased (P < 0.05) the contents of malondialdehyde and H2O2 in liver. DMG-Na supplementation increased (P < 0.05) body weight gain, feed intake, and feed efficiency, decreased (P < 0.05) ALT and AST activities, and reduced the content of H2O2 in LBW piglets. LBW piglets had downregulated (P < 0.05) mRNA expression of thioredoxin 2, thioredoxin reductases 2, and nuclear respiratory factor-1 (Nrf1) in the liver. However, DMG-Na supplementation increased (P < 0.05) mRNA expression of Nrf1 in the liver. In conclusion, DMG-Na supplementation has beneficial effects in alleviating LBW-induced hepatic oxidative damage and changed mitochondrial genes expression levels, which is associated with increased antioxidant enzyme activities and up-regulating mRNA gene abundance.