ACC	acetyl-CoA carboxylase
AceCS	acetyl-CoA synthetase
AGEs	advanced glycation end products
AIFM2	factor mitochondria associated 2A
ALP	alkaline phosphatase
ALT	alanine aminotransferase
AMPK	AMP-activated protein kinase
ArgP	Argpyrimidine
ApoE−/−	apolipoprotein E knockout
AST	aspartate aminotransferase
ATAUC	adipose tissuearea under the curve
α-SMA	alpha-smooth muscle actin
BCAA	Branched-chain amino acids
CaMKKβ	Ca21/calmodulin-dependent protein kinase kinase β
CCl4	carbon tetrachloride
CD43	leukosialin (mucin-like protein expressed on the surface of most hematopoietic cells)
CEdG	N2-carboxyethyl-20–deoxyguanosine
CEL	Nε-(1-carboxyethyl)lysine = N6-(1-carboxyethyl)lysine
Chol	Cholesterol
ChREBP	carbohydrate-responsive element-binding protein
CRP	C-reactive protein
CTGF	connective tissue growth factor
CVD	cardiovascular disease
DAGs	Diacylglycerols
DAMPs	damage-associated molecular patterns
DMT1	divalent metal transporter 1
DNL	de novo lipogenesis
ECM	extracellular matrix
EVsFAs	extracellular vesiclesfatty acids
FAS	fatty acid synthase
Fru	Fructose
FXR	farnesoid X receptor
GA	Glyceraldehyde
GAPDH	glyceraldehyde-3-phosphate dehydrogenase
GGT	γ-glutamyl transpeptidase
GIT	gastrointestinal tract
Glc	Glucose
Glo1	glyoxalase 1
Glo2	glyoxalase 2
GLUT-4	insulin-dependent glucose transporters in skeletal muscle and adipose tissue
GPx	glutathione peroxidase
GPX4	glutathione peroxidase 4
GSH	reduced glutathione
GSSG	oxidized glutathione
HCC	hepatocellular carcinoma
HDL-Chol	high-density lipoproteins cholesterol
Hep G2	epithelial hepatoblastoma cell line
HFCS	high-fructose corn syrup
HFD	high-fat diet
HHTg	hereditary hypertriglyceridemic rats
HIF	hypoxia-inducible factor
HO	heme oxygenase
HOMA	homeostatic model assessment
HSCs	hepatic stellate cells
IR	insulin resistance
IRS-1,2	insulin receptor substrate 1,2
JNK	c-jun NH2-terminal kinase
KCs	Kupffer cells
LKB1	liver kinase B1
LPO	lipid peroxidation
LPS	Lipopolysaccharide
LSECs	liver sinusoidal endothelial cells
MAGEs	MGO-derived advanced glycation end products
MAPKs	mitogen-activated protein kinases
MASLD	metabolic dysfunction-associated fatty liver disease
MCP-1	monocyte chemoattractant protein 1
MDA	Malondialdehyde
MetS	metabolic syndrome
MG-dG	3-(20–deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purin-9(8)one
MG-H1	Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine
MG-H2	2-amino-5-(2-amino-5-hydro-5-methyl-4- imidazolon-1-yl)-pentanoic acid
MG-H3	2-amino-5-(2-amino-4-hydro-4-methyl-5-imidazolon-1-yl)-pentanoic acid
MGO	Methylglyoxal
MKK7	mitogen-activated protein kinase kinase 7
NEFAs	non-esterified fatty acids
NF-κB	nuclear factor-kB
NOX	NADPH oxidase
Nrf2	nuclear factor erythroid 2-related factor 2
PARP	poly(ADP-ribose) polymerase
PRRs	pattern recognition receptors
PUFAs	polyunsaturated fatty acids
p38 MAPK	p38 mitogen-activated protein kinase
RAGE	advanced glycation end products receptor
RCS	reactive carbonyl species
RCT	randomized controlled trial
RNS	reactive nitrogen species
ROS	reactive oxygen species
SCFAs	short chain fatty acids
SMAD3	a protein involved in TGF-β signal transduction
SOD	superoxide dismutase
SREBP	sterol regulatory element-binding protein
TAGs	Triacylglycerols
TAK1	TGF-β-activated kinase 1
TBARS	thiobarbituric acid reactive substances
TC	total cholesterol
TCA	tricarboxylic acid cycle (Krebs cycle)
T2DM	type 2 diabetes mellitus
TfR1	transferrin receptor 1
TGF-β	transforming growth factor β
THP	Tetrahydropyrimidine
TNFα	tumor necrosis factor alfa
THR-β	thyroid hormone receptor β
Trx	Thioredoxin
WR	Wistar rats
Glossary
Term	Definition
AMPK	AMP-activated protein kinase is an energy sensor which regulates metabolism, switching the processes between catabolic and anabolic depending on the energetic status of the cell. AMPK requires threonine (Thr172) phosphorylation for its activation, which is achieved by three different kinases (liver kinase B1—LKB1, Ca21/calmodulin-dependent protein kinase kinase β—CaMKKβ, and TGF-β-activated kinase 1—TAK1) induced by various signals [48]. AMPK is sustained in this active phosphorylated formed at low energy level by AMP (and ADP) binding, whereas higher ATP concentration inactivates the enzyme. Therefore, at low energy levels reflected by high AMP/ATP ratio, AMPK is active and regulates specific target enzymes, increasing lipid oxidation and mitochondrial biogenesis, whereas the synthesis of lipids and glycogen is inhibited. In such a way, energy-consuming anabolic pathways are attenuated in favor of induced catabolic pathways aimed at the replenishment of energy. One of the important targets of AMPK is acetyl-CoA carboxylase (ACC) which produces malonyl-CoA. Malonyl-CoA is a substrate for palmitic acid synthesis, but also it is an inhibitor of carnitine palmitoyl-transferase 1 (CPT1)—an enzyme involved in the transport of long-chain fatty acids to the mitochondrium for β-oxidation. AMPK phosphorylates and inhibits ACC which leads to a decrease in malonyl-CoA, thus attenuating palmitic acid synthesis. Simultaneously, a drop in malonyl-CoA level releases the inhibition of CPT1 which enables entry of FAs to the mitochondrium for β-oxidation. Consequently, the synthesis of fatty acids (DNL) in the liver decreases, whereas mitochondrial β-oxidation of FAs increases [48,49]. Additionally, AMPK phosphorylates and inhibits transcription factors (sterol regulatory element-binding proteins, SREBPs) responsible for the expression of enzymes involved in FAs, triacylglycerol, and cholesterol synthesis.
Apoptosis	Apoptosis is a type of regulated cell death necessary for the clearance of destroyed cells to maintain tissues in healthy condition. Damaged cells undergo shrinking and membrane blebbing, followed by the removal of macrophages. Apoptosis can be induced by internal or external signals. The intrinsic (mitochondrial) pathway is initiated by receptor-independent signals generated in the cell, such as ROS accumulation. The major regulator detecting DNA damages and deciding on the further cell’s fate is the tumor suppressor p53 protein. This protein controls Bcl-2 family proteins. Bcl-2 and Bcl-XL belong to pro-survival factors, whereas Bax or Bak stimulate apoptotic events. In response to strong proapoptotic signals (e.g., resulting from the accumulation of unrepairable genetic defects), they increase the permeability of the inner mitochondrial membrane and release of proapoptotic factors, including cytochrome C. Extrinsic pathways are induced by death receptors which activate caspase cascade starting from caspase 8. Both intrinsic and extrinsic pathways converge on the execution phase initiated by the activation of caspase 3 [245].
Autophagy	Autophagy (“self-eating”) is a conservative, pro-survival process employed by normal cells to recycle the wastes (defective or unnecessary intracellular structures and macromolecules). It is divided into macroautophagy, selective autophagy, microautophagy, and chaperone-mediated autophagy, from which macroautophagy—the most common and best studied type is usually referred to as simply autophagy [77]. Macroautophagy proceeds with the formation of an autophagosome (a sequestration of a fragment of cytoplasm by surrounding its contents with double membranes) which next fuses with a lysosome yielding autophagolysosome. Lysosomal hydrolases degrade enclosed molecules generating products which are exported back into the cytoplasm where they are reused for the synthesis of new molecules, such as amino acids for novel protein formation. Degradation products also serve as a source of energy (e.g., fatty acids). Autophagy functions constitutively at a low level, but in conditions of nutrients and/or oxygen deprivation as well as ER stress it intensifies to increase the survival odds in stressful conditions. Signaling pathways regulating these events include mammalian targets of rapamycin (mTOR), as well as AMPK routes. mTOR being active at sufficient nutrient satiation suppresses the induction of autophagy, whereas, during starvation, inflowing signals block the mTOR route, which triggers the autodigestion mechanism. In turn, AMPK being the sensor of intracellular energy level, becomes activated at ATP depletion, therefore it induces autophagy during energy exhaustion [246,247].
De novo lipogenesis (DNL)	De novo lipogenesis is the process of converting excess dietary carbohydrates (mainly Glc and Fru) into fatty acids. FAs are produced from acetyl-CoA molecules generated in carbohydrate catabolism (in glycolysis from Glc and fructolysis from Fru) or acetate generated by microbiota Fru fermentation [36,37].
Ferroptosis	Ferroptosis is a type of non-apoptotic regulated cell death stimulated by iron-dependent lipid peroxidation and characterized by cell swelling and plasma membrane rupture. It is promoted under conditions of a high concentration of free iron, ROS, and membrane phospholipids containing polyunsaturated fatty acids (PUFAs). Free iron in the presence of superoxide radicals leads to the generation of hydroxyl radicals which stimulates lipid (PUFAs) peroxidation. This causes degradation of biological membranes and cell death. Therefore, the upregulation of factors which increase iron and ROS accumulation promotes ferroptosis. They include proteins involved in iron transport and generation (e.g., transferrin receptor or heme oxygenase—HO), as well as superoxide production (like NADPH oxidases—NOXs). Ferroptosis can also be promoted by selective autophagy such as ferritinophagy and lipophagy which are associated with the release of iron cations and fatty acids, respectively. In turn, the main mechanism restraining ferroptosis includes glutathione peroxidase 4 (GPX4)—a selenium-dependent antioxidative enzyme which reduces phospholipid hydroperoxides, as well as reduced glutathione—a co-substrate in GPX4 reaction. The sufficient level of GSH in the cell is conditioned by the influx of its precursor—cystine. Therefore, the transporter (xc- antiporter) involved in cystine transport to the cells plays an important function here. Another component protecting from ferroptosis is a apoptosis-inducing factor for mitochondria associated 2A (AIFM2/FSP1) protein, which seems to act in two ways. Firstly, having an oxidoreductase activity, AIFM2 reduces coenzyme Q10 to its ubiquinol form, which generates a hydrophobic antioxidant. Secondly, it protects from membrane injury through activating the endosomal sorting complexes required for transport (ESCRT)-III–dependent membrane repair in the plasma membrane [47].
Lipophagy	Lipophagy is a type of selective autophagy controlling lipid metabolism. It proceeds through the surrounding of lipid droplets by a double membrane (autophagosome) which further fuses with the lysosome. Subsequently, lysosomal lipases hydrolyze lipid contents releasing their products, e.g., fatty acids. Fatty acids are directed to the mitochondrium for β-oxidation [248,249].
Mitophagy	Mitophagy is a type of selective autophagy responsible for a steady-state turnover of mitochondria as well as the clearance of injured mitochondria. Damage to mitochondria (reflected by the loss of the mitochondrial membrane potential), induces Parkin (E3 ubiquitin ligase) translocation to mitochondria. Parkin ubiquitinates outer membrane proteins which induce mitophagy. Subsequently, the mitochondrium become surrounded by a double membrane (autophagosome) and fuse with the lysosome whose hydrolases degrade mitochonrium components. Parkin recruitment is mediated by PINK1 [247].