Epigallocatechin gallate but not catechin prevents nonalcoholic steatohepatitis in mice similar to green tea extract while differentially affecting the gut microbiota.

Catechin-rich green tea extract (GTE) protects against nonalcoholic steatohepatitis (NASH) by alleviating gut-derived endotoxin translocation and hepatic Toll-like receptor-4 (TLR4)-nuclear factor κB (NFκB) inflammation. We hypothesized that intact GTE would attenuate NASH-associated responses along the gut-liver axis to a greater extent than purified (-)-epigallocatechin gallate (EGCG) or (+)-catechin (CAT). Male C57BL/6J mice were fed a low-fat diet, a high-fat (HF) diet, or the HF diet with 2% GTE, 0.3% EGCG or 0.3% CAT for 8 weeks prior to assessing NASH relative to endotoxemia, hepatic and intestinal inflammation, intestinal tight junction proteins (TJPs) and gut microbial ecology. GTE prevented HF-induced obesity to a greater extent than EGCG and CAT, whereas GTE and EGCG more favorably attenuated insulin resistance. GTE, EGCG and CAT similarly attenuated serum alanine aminotransferase and serum endotoxin, but only GTE and EGCG fully alleviated HF-induced NASH. However, hepatic TLR4/NFκB inflammatory responses that were otherwise increased in HF mice were similarly attenuated by GTE, EGCG and CAT. Each treatment also similarly prevented the HF-induced loss in expression of intestinal TJPs and hypoxia inducible factor-1α and the otherwise increased levels of ileal and colonic TNFα mRNA and fecal calprotectin protein concentrations. Gut microbial diversity that was otherwise lowered in HF mice was maintained by GTE and CAT only. Further, microbial metabolic functions were more similar between GTE and CAT. Collectively, GTE catechins similarly protect against endotoxin-TLR4-NFκB inflammation in NASH, but EGCG and CAT exert differential prebiotic and antimicrobial activities suggesting that catechin-mediated shifts in microbiota composition are not entirely responsible for their benefits along the gut-liver axis.

Green tea extract inhibits early oncogenic responses in mice with nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) increases hepatocellular carcinoma (HCC) risk. We hypothesized that the hepatoprotective anti-inflammatory benefits of catechin-rich green tea extract (GTE) would protect against HCC progression by inhibiting NASH-associated liver injury and pro-oncogenic responses. We used an HCC model in high-fat (HF)-fed mice that mimics early oncogenic events during NASH without inducing tumorigenesis and premature mortality. Male C57BL/6J mice (4-weeks old) were fed a HF diet containing GTE at 0% or 2%. Mice were administered saline or diethylnitrosamine (DEN; 60 mg kg-1, i.p.) at 5-weeks and 7-weeks of age. NASH, inflammation, fibrosis, and oncogenic responses were assessed at 25-weeks of age. Saline-treated mice showed prominent histopathological signs of steatosis and hepatocellular ballooning. Although DEN did not impact adiposity, steatosis, ballooning and hepatic lipid accumulation, these parameters were attenuated by GTE regardless of DEN. Hepatic lipid peroxidation and fibrosis that were increased by DEN were attenuated by GTE. Hepatic TLR4, MCP1 and TNFα mRNA levels were unaffected by DEN, whereas iNOS was increased by DEN. These transcripts were lowered by GTE. GTE attenuated the frequency of PCNA+ hepatocytes and mRNA expression of cyclin D1, MIB1 and Ki-67 that were otherwise increased by DEN. GTE increase APAF1 mRNA that was otherwise lowered by DEN. Relative to saline-treated mice, DEN increased mRNA levels of oncostatin M, gp130, c-Fos, c-Myc and survivin; each was lowered by GTE in DEN-treated mice. These findings indicate that GTE may protect against hepatic oncogenesis by limiting early steps in the carcinogenic cascade related to NASH-associated HCC.

Dairy milk, regardless of fat content, protects against postprandial hyperglycemia-mediated impairments in vascular endothelial function in adults with prediabetes by limiting oxidative stress responses that reduce nitric oxide bioavailability.

Postprandial hyperglycemia (PPH) transiently impairs vascular endothelial function (VEF) in an oxidative-stress-dependent manner by decreasing nitric oxide (NO•) bioavailability. Dairy milk, regardless of fat content, attenuates PPH, but whether this improves VEF by limiting oxidative stress responses that otherwise decrease NO• bioavailability is not known. We hypothesized that nonfat and full-fat dairy milk would similarly improve VEF by attenuating PPH-induced oxidative stress that otherwise decreases NO• biosynthesis and bioavailability. A randomized, crossover trial was conducted in adults with prediabetes (n=22) who ingested glucose (75 g) dissolved in 473 ml of water (GLU), or glucose with an equal volume of nonfat dairy milk (NFM) or full-fat dairy milk (FFM). Prior to and at 30-min intervals for 180 min postprandially, we assessed brachial artery flow-mediated dilation (FMD) and measured circulating biomarkers of glycemic control, oxidative stress and NO• homeostasis. AUC0-180 min for FMD and NO• metabolites was lowest in GLU but relatively greater in NFM and FFM. Compared with GLU, AUCs for glucose, malondialdehyde, F2-isoprostanes and endothelin-1 were similarly lower in dairy trials. Milk-mediated vasoprotection was accompanied by greater levels of plasma arginine and lower levels of asymmetric dimethylarginine and symmetric dimethylarginine. Postprandial insulin, lipids and tetrahydrobiopterin redox status did not differ among trials. Thus, dairy milk, regardless of its fat content, attenuates PPH-mediated impairments in VEF by limiting oxidative stress. This improves NO• bioavailability to the vascular endothelium by increasing arginine availability and limiting competitive inhibition on NO• biosynthesis by asymmetric dimethylarginine.