Table 2.

Proanthocyanidin-mediated functions and mechanisms to reduce the NAFLD risk.

Experimental Model	Biological Functions and Mechanisms	Reference
(1) Supplementation of NAFLD patients with PAC-rich grape seed extract (200 mg twice per day) for 2 months.	Ameliorate hyperlipidemia by reducing triglyceride, LDL, and cholesterol levels and increasing HDL levels. Reduce the fasting blood sugar level. Mitigate hepatic injury (as depicted by the low ALT and AST levels).	[171]
(2) C57BL/6 mice were supplemented with the cranberry PAC (200 mg/kg bw/day) and an HFHS diet concomitantly for 12 weeks.	Reduce hepatic lipogenesis by downregulating the expression of SERBP-1c, ChREBP, and FAS. Promote hepatic FA oxidation by upregulating the expressions of CPT-1, PPAR-α, and PGC-1α. Mitigate hepatic inflammation by suppressing NF-κB mediated production of proinflammatory TNF-α and COX-2. Alleviate oxidative stress by upregulating the expressions of GPx, SOD, and Nrf2.	[174]
(3) Wistar rats induced for NAFLD by feeding with an HFHF diet for 30 days were supplemented with grape seed PAC (100 mg/kg bw/day) for another 15 days concomitantly with the HFHF diet.	Reduce hepatic steatosis by downregulating the expressions of lipogenic SREBP-1c and the lipid droplet proteins, FSP27, perilipins, and adipophilin. Promote FA oxidation by upregulating the expression of PPAR-α. Reduce cholesterol synthesis by downregulating the expression of the HMG-CoA reductase enzyme.	[176]
(4) Sprague Dawley rats were fed with an HFD for 8 weeks to induce obesity. The mice were supplemented with grape seed PAC (500 mg/kg bw/day) and HFD concomitantly for 4 weeks.	Mitigate hepatic steatosis by downregulating the expression of PPAR-γ. Alleviate ER stress response (the UPR) by downregulating the expressions of ATF6 and CHOP at the mRNA level. Reduces apoptosis-mediated hepatic injury by upregulating the expression of antiapoptotic BCL-2. Alleviate hepatic inflammation by downregulating the expressions of IL-1β and TNF-α.	[175]
(5) HepG2 and L02 liver cells were exposed to a mixture of oleic and palmitic acids (0.2 mM for 24 h) and treated with procyanidin B2 (2.5–10 µg/mL for 24 h). C57BL/6 mice were fed with an HFD for 10 weeks to induce obesity. Then, mice were administered procyanidin B2 (50 and 150 mg/kg bw/day) and fed with the HFD concomitantly for 10 weeks.	Promote hepatic lipid degradation by activating the TFEB-mediated lysosomal pathway. Mitigate hepatic oxidative stress by scavenging ROS and superoxide anion radicals, protecting the mitochondria membrane potential, preventing glutathione depletion, and increasing the activity of GPx, SOD, and CAT antioxidant enzymes. May reduce hepatic steatosis by restoring hepatic TFEB expression and subsequent lipid degradation by the lysosomal pathway. Mitigate hepatic steatosis by reducing the expressions of PPAR-γ, C/EBPα, and SREBP-1c. Alleviate hepatic oxidative stress by increasing the activity of GPx, SOD, and CAT. Mitigate hepatic inflammation by reducing the production of proinflammatory cytokines, IL-6 and TNF-α.	[177]
(6) An LPS-injected mouse model to evaluate intestinal inflammation. C57BL/6 mice were supplemented with grape seed PAC (250 mg/kg bw/day) for 20 days.	Improve the gut microbiota by increasing bacteria richness and diversity. Increase the mRNA expressions of the bile acid receptor FXR and its targets FGF15 and SHP by modulating the gut microbiota-mediated bile acid metabolism.	[178]
(7) C57BL/6 mice were fed with an HFD containing procyanidin B2 (0.2% w:w) for 8 weeks.	Increase the activity of hepatic antioxidant enzymes CAT and SOD. Improve gut microbiota by reducing the abundance of Firmicutes and increasing the abundance of Bacteroidetes. Promote the production of SCFA, propionic, and butyric acids by the gut microbiota.	[179]
(8) C56BL/6J mice were fed with an HFD and administered with PAC isolated from bayberry leaves (100 mg/kg bw/day) for 8 weeks.	Mitigate hepatic lipid accumulation by downregulating the expressions of lipogenic SREBP-1c, ACC, and FAS. Increase FA oxidation by upregulating the expressions of PPAR-α and CPT-1. Increase the blood serum concentration of adiponectin and reduce the concentration of leptin. Protect gut-epithelial barrier function in the ileum and colon by upregulating the expressions of tight junction proteins, ZO-1 and occludin. Reduce the level of circulating LPS and the production of proinflammatory cytokines, IL-6 and TNF-α, in the liver and white adipose tissue.	[180]

ACC, acetyl-CoA carboxylase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATF6, activating transcription factor-6; BCL-2, B-cell lymphoma 2; bw, body weight; C/EBPα, CCAAT-enhancer-binding protein α; CAT, catalase; CHOP, C/EBP-homologous protein; ChREBP, carbohydrate response element-binding protein; COX-2, cycloogenase-2; CPT-1, carnitine-palmitoyl-transferase-1; ER, endoplasmic reticulum; FA, fatty acid; FAS, fatty acid synthase; FGF15, fibroblast growth factor 15; FSP27, fat specific protein 27; FXR, farnesoid X receptor; GPx, glutathione peroxidase; HDL, high-density lipoprotein; HFD, high-fat diet; HFHF, high-fat and high-sucrose; HFHS, high-fat and high-sucrose; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; IL, interleukin; LDL, low-density lipoprotein; LPS, lipopolysaccharide; NAFLD, nonalcoholic fatty liver disease; Nrf2, nuclear factor erythroid 2-related factor 2; PAC, proanthocyanidin; PGC-1α, PPAR-γ coactivator-1α; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; SCFA, short-chain fatty acid; SHP, small heterodimer partner; SOD, superoxide dismutase; SREBP-1c, sterol regulatory element binding protein-1c; TFEB, transcription factor EB; TNF-α, tumor necrosis factor-α; UPR, unfolded protein response; ZO-1, zonula occludens-1.