Hepatocyte nuclear factors dynamically regulate triglyceride metabolic reprogramming in metabolic dysfunction-associated steatotic liver disease: Mechanisms and implications

Table 1 Core metabolic differences between obesity-related and lean metabolic dysfunction-associated steatotic liver disease

Characteristic	Obesity-related MASLD	Lean MASLD
Primary initiating factors	Systemic IR, overnutrition	Genetic variants, dysfunctional visceral adipose tissue, and gut-liver axis dysregulation
FFA source	Peripheral lipolysis	Visceral adipose tissue, gut microbiota-derived metabolites
DNL	Enhanced	Enhanced
Fatty acid oxidation	Impaired	May be markedly reduced
VLDL	Early compensatory increase (relative insufficiency), later absolute insufficiency	Genetic secretion defects (e.g., TM6SF2 variants) or normal
Inflammatory triggers	Early adipose tissue macrophage activation, later accompanied by hepatic innate immune activation	Gut-derived LPS translocation, hepatic innate immune activation
Genetic predisposition	Polygenic susceptibility with cumulative minor effects	Monogenic strong effects (e.g., PNPLA3)
Prognosis	Higher incidence of cardiovascular complications	Higher incidence of liver disease and all-cause mortality
Clinical management focus	Weight reduction, improving IR, managing metabolic syndrome	Fructose restriction, correcting malnutrition, targeted genetic interventions

MASLD: Metabolic dysfunction-associated steatotic liver disease; IR: Insulin resistance; FFA: Free fatty acid; DNL: De novo lipogenesis; VLDL: Very low-density lipoprotein; TM6SF2: Transmembrane 6 superfamily member 2; LPS: Lipopolysaccharide; PNPLA3: Patatin-like phospholipase domain-containing protein 3.

Table 2 Role of hepatocyte nuclear factors in triglyceride metabolism in metabolic dysfunction-associated steatotic liver disease

HNF	Model	Target	Mechanism	Main results	Ref.
HNF-1α	C57BL/6J mice	L-FABP↑	Promotes the transport of long-chain fatty acids from the intracellular space to specific organelles	Promotes lipid synthesis	[133]
	C57BL/6J mice	PPAR-γ↓	Reduces synthesis of TGs and Cho	Inhibits lipid synthesis	[126]
	C57BL/6J mice	SREBP-1c↓	Inhibits the expression of its target lipogenesis genes	Inhibits TG synthesis	[130]
	HepG2 cells and Huh7 cells	Sigma receptor 1↓	Decreases intracellular lipid droplet formation rate and lipid storage capacity	Inhibits lipid synthesis	[136]
	C57BL/6J mice	PCSK9↑	Mediates degradation of LDL receptors and increases plasma LDL-C levels	Reduces Cho intake	[142]
	-	CYP7A1↑, BSEP↑, NTCP↑	Promotes the elimination of BAs	Reduces Cho accumulation	[143]
	HepG2 cells	MiR-122↓	Enhances miR-122-inhibited SCAP expression and interferes with SREBP-2 maturation	Reduces lipid synthesis and absorption	[130]
HNF-1β	-	Angiopoietin-like protein 8↑	Inhibits LPL activity	Reduces TG hydrolysis	[147,148]
	3T3-L1 preadipocytes	PPAR-γ↓	Enhances mitochondrial oxidative phosphorylation	Accelerates TG decomposition	[149]
	C57BL/6J mice	GPX1↑	Reduces ROS levels, which in turn reduces the expression of SREBP-1, ACC, and FASN	Indirectly inhibits TG synthesis	[151]
	AML-12 cells	SREBP-1c↓	Inhibits the expression of its target lipogenesis genes	Inhibits lipid synthesis	[146]
FOXA1	HepG2 cells	GPAT1↓, DGAT2↓, MTP↓, ApoB↓	Inhibits the expression of its target genes related to TG synthesis and secretion	Inhibits TG synthesis and secretion	[157]
	HepG2 cells	FABP1↑	Activates its transcription	Promotes intracellular transport of fatty acids	[158]
	HepG2 cells	UCP1↑	Enhances its expression and reduces mitochondrial membrane potential	Reduces lipid storage	[157]
	HepG2 cells	HMGCS2↑	Enhances ketone production	Promotes TG catabolism	[157]
FOXA2	HepG2 cells	hFABP1↑	Activates its transcription	Involved in the transport of long-chain fatty acids	[160]
	-	PGC-1β↑	Activates mitochondrial fatty acid oxidation	Enhances FA metabolism	[166]
FOXA3	C57BL/6J mice	ApoA-1↑	Mediates reverse Cho transport by macrophages	Promotes liver cell steatosis	[173]
HNF-4α	HFD mice	ApoB↓	Reduces secretion of VLDL	Promotes lipid accumulation	[187]
	C57BL/6J mice	ULK1↑	Activates lipophagy	Reduces lipid storage	[199]
	HFD mice	CDKL3↑	Induces phosphorylation of FoxO1	Reduces lipid accumulation	[207]
HNF-6	BDL mice	CYP7A1↓	Reduces Cho-to-BA conversion	Severely impairs Cho clearance	[208]

HNF: Hepatocyte nuclear factor; L-FABP: Liver fatty acid-binding protein; PPAR: Peroxisome proliferator-activated receptor; TG: Triglyceride; Cho: Cholesterol; SREBP-1c: Sterol regulatory element-binding protein-lc; PCSK9: Proprotein convertase subtilisin/kexin type 9; LDL: Low-density lipoprotein; LDL-C: Low-density lipoprotein-cholesterol; CYP7A1: Cholesterol 7α-hydroxylase; BSEP: Bile salt export pump; NTCP: Sodium taurocholate cotransporting polypeptide; SCAP: Sterol regulatory element-binding protein cleavage-activating protein; GPX: Glutathione peroxidase; ROS: Reactive oxygen species; ACC: Acetyl-CoA carboxylase; FASN: Fatty acid synthase; FOXA: Forkhead box A; GPAT1: Glycerol-3-phosphate acyltransferase 1; DGAT2: Diacylglycerol acyltransferase 2; MTP: Microsomal triglyceride transfer protein; ApoB: Apolipoproteins B; FABP1: Fatty acid binding protein 1; UCP1: Uncoupling protein 1; HMGCS2: 3-hydroxy-3-methylglutaryl-CoA synthase 2; hFABP1: Human liver fatty acid-binding protein 1; PGC-1β: Peroxisome proliferator-activated receptor gamma coactivator-1β; FA: Fatty acid; VLDL: Very low-density lipoprotein; HFD: High fat diet; ULK1: Unc-51-like autophagy activating kinase 1; CDKL3: Cyclin-dependent kinase-like 3; FoxO1: Forkhead box protein O1.