Targeting the gut microbiota and lipid metabolism: potential mechanisms of natural products for the treatment of non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic progressive liver disease with overnutrition and insulin resistance (IR) as the main etiologic factors. Hepatic lipid accumulation is a central factor contributing to this cascade of changes. Consequently, therapeutic interventions that target hepatic lipid metabolism and inflammatory response pathways hold considerable promise for the treatment of NAFLD. Furthermore, there is a close link between the gut microbiota (GM) and host health. GM and its metabolites can rely on multiple complex pathways to be deeply involved in the occurrence and development of NAFLD, which is associated with a variety of mechanisms. This makes it difficult to achieve satisfactory therapeutic efficacy of drugs targeting a single specific mechanism. In this context, natural products have the advantage of intervening in multiple targets and high safety. Consequently, an increasing number of researchers are considering natural products as a potential breakthrough point for the treatment of NAFLD. Notably, natural products influence intestinal mucosal permeability and metabolite production by regulating the abundance of beneficial flora in GM, which in turn regulates lipid metabolism to reduce hepatic steatosis and inhibit the progression of NAFLD. This paper reviews the research progress of natural products intervening in NAFLD through GM and its metabolites and lipid metabolism that has emerged in recent years, aiming to provide a basis for future natural product interventions in NAFLD.

Keywords: NAFLD; gut microbiota; lipid metabolism; natural products; probiotics.

FIGURE 1

The thickness of the arrow represents the quantity in this figure. Possible mechanisms of the role of fatty acid metabolism in the development of NAFLD. Fatty acid metabolism is one of the important links in liver lipid metabolism, and its balance affects the progression of NAFLD. Fatty acid metabolism includes the uptake of circulating FFA, de novo lipogenesis (DNL), fatty acid β-oxidation (FAO), and the release of FFAs into the bloodstream in the form of very low-density lipoproteins (V-LDL). The first two increase the amount of fatty acids in the liver, while the latter two consume the amount of fatty acids in hepatocytes. When the increase in fatty acids is greater than the consumption, it will drive the development of NAFLD. NAFLD, non-alcoholic fatty liver disease; FATP, fatty acid transport protein; FABP, fatty acid-binding proteins; CAV-1, Caveolin-1; CD36, cluster of differentiation 36; FAO, fatty acid oxidation; TCA, tricarboxylic acid; FAS, fatty acid synthesis; DNL, de novo lipogenesis; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; SCD1, stearoyl-CoA desaturase1; Dgat2, diacylgycerol acyltransferase; ACSL, acyl-CoA synthetaselong chain family member; PPARα, peroxisomeproliferator-activated receptor alpha; CPT1, carnitine palmitoyltransferase 1; MTTP, microsomal triglyceride transfer protein; tPA, tissue plasminogen activator; VLDL, very low density lipoprotein.

FIGURE 2

BAs contribute to host metabolism in various organs through FXR and TGR5. BAs synthesis in the liver and glucose metabolism are regulated by the intestinal FXR-FGF15/19 signal, and BAs also affect lipid synthesis in the liver through the FXR-SHP signal pathway. In addition, BAs enhance host energy metabolism through TGR5, including driving BAT thermogenesis; promoting the conversion of inactive thyroxine (T4) to active thyroid hormone (T3) in skeletal muscle to increase energy consumption; and promoting the release of GLP-1 and PYY by colon L cells to improve IR and suppress appetite. SCFAs promote BAT thermogenesis by activating PGC-1α and UCP-1 in adipose tissue. Secondly, SCFAs activate AMPK in the liver, on the one hand, SCFAs can downregulate DNL by inhibiting SREBP-1c and thereby reducing the expression of ACC and FASN, and on the other hand, they can promote FAO by activating PPARα and thereby upregulating the expression of CPT1α. In addition, SCFAs can reduce intake by activating GPR41/43 in the intestine to release PYY and GLP-1, and reduce lipid uptake through ABCG5/8 and NPC1L1, thereby increasing lipid excretion in the feces. TMAO enhances the pro-inflammatory polarization of macrophages and the release of inflammatory factors. TMAO inhibits the conversion of TC to BAs through the liver FXR/SHP signaling pathway. The balance of the intestinal microecology and the diversity of GM help to stabilize the intestinal mucosal barrier and immune system. BAs, bile acids; FXR, farnesoid X receptor; TGR5, G proteincoupled bile acid receptor; FGF15/19, fibroblast growth factor 15/19; FGFR4, fibroblast growth factor receptor 4; NTCP, sodium dependent taurocholate co-transporting polypeptide; OSTα/β, organic solute transporter subunit α/β; DIO2, Type II iodothyronine deionidinase; SHP, small heterodimer partner; BAT, brown adipose tissue; GLP-1, glucagon-like peptide-1; PYY, peptide YY; SCFAs, short chain fatty acid; PGC-1α, Peroxisome proliferator-activated receptor-γ coactivator-1α; UCP-1, Uncoupling protein 1; AMPK, AMP-activated protein kinase; SREBP-1c, sterol regulatory element-binding protein-1c; ACC, acetyl-co carboxylase; FASN, fatty acid synthase; PPARα, Peroxisome proliferator-activated receptor α; CPT1α, carnitine palmitoyltransferase-1 α; GPR41/43, G protein-coupled receptors 41/43; ABCG5/8, ATP-binding cassette transporter G5/8; NPC1L1, Niemann-Pick type C1 like1; TMAO, Trimethylamine oxide; TC, cholesterol; GM, gut microbiota.

FIGURE 3

An overview of the therapeutic effects of natural products on NAFLD through regulation of glucose and lipid metabolism. Imbalances in liver lipid metabolism (the accumulation of lipids in the liver exceeds their consumption) can trigger the progression of NAFLD. Natural products regulate liver imbalances through the gut microbiota, promoting lipid metabolism balance in the liver, which helps reverse the progression of NAFLD. NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.