Metabolic dysfunction-associated steatotic liver disease and omega-6 polyunsaturated fatty acids: Friends or foes

Table 1 Biochemical structure of omega-6 subtypes

Omega family	Common name	Systematic name	Abbreviations
n-6	LA	all-cis-9,12-octadecadienoic acid	18:2n-6 or 18:2
	GLA	all-cis-6,9,12-octadecatrienoic acid	18:3n-6 or 18:3
	DGLA	all-cis-8,11,14-eicosatrienoic acid	20:3n-6 or 20:3
	AA	all-cis-5,8,11,14-eicosatetraenoic acid	20:4n-6 or 20:4
	DTA	all-cis-7,10,13,16-docosatetraenoic acid	22:4n-6 or 22:4
	Tetracosatetraenoic acid (TTA n-6)	all-cis-9,12,13 ,5,18-tetracosatetraenoic acid	24:4n-6 or 24:4
	Tetracosapentaenoic acid (TPA n-6)	all-cis-6,9,12,15,18-tetracosapentaenoic acid	24:5n-6 or 24:6
	DPA n-6	all-cis-4,7,10,13,16-docosapentaenoic acid	22:5n-6 or 22:5

LA: Linoleic acid; GLA: Gamma-linolenic acid; DGLA: Dihomo-gamma-linolenic acid; AA: Arachidonic acid; TTA _n-6: Tetracosatetraenoic acid; TPA _n-6: Tetracosapentaenoic acid; DPA _n-6: Docosapentaenoic acid.

Table 2 Studies reporting connection between metabolic dysfunction-associated steatotic liver disease (also called non-alcoholic fatty liver disease) and omega-6 polyunsaturated fatty acids

Ref.	Title	Number of cases (human or animal)	Key findings	Results related to MASLD
Montemayor et al[51], 2023	Dietary patterns, foods, and nutrients to ameliorate non-alcoholic fatty liver disease	Review article	The mediterranean diet, high in PUFAs, improves MASLD; sugar-free coffee may be protective; high-quality diet improves liver steatosis	Mediterranean diet rich in omega-6 helps reduce liver fat and inflammation; sugar-free coffee may also help protect against MASLD
Tian et al[50], 2023	Associations between dietary fatty acid patterns and non-alcoholic fatty liver disease in typical dietary population: A United Kingdom biobank study	93399 cases (human study)	PUFA-enriched vegetarian diet negatively associated with NAFLD; animal-source PUFA diet not significantly associated with NAFLD	Vegetarian diet high in omega-6 associated with lower NAFLD risk; animal based PUFA diet not significantly associated with NAFLD risk
Van Name et al[46], 2020	A low ω-6 to ω-3 PUFA ratio (n-6:n-3 PUFA) diet to treat fatty liver disease in obese youth	20 obese adolescents (human study)	A low n-6:n-3 PUFA ratio diet significantly reduced hepatic fat fraction, ALT, and triglycerides in obese youth with NAFLD	The study demonstrated significant improvement in hepatic steatosis and glucose metabolism in obese youth with NAFLD
Heinzer et al[49], 2022	Dietary omega-6/omega-3 ratio is not associated with gut microbiota composition and disease severity in patients with nonalcoholic fatty liver disease	101 NAFLD (human study)	An increased n-6/n-3 ratio in the diet of NAFLD patients is not associated with gut microbiota composition and disease severity	The associations between the dietary n-6/n-3 ratio, the gut bacterial composition, and the disease severity of NAFLD remained unclear
Banaszczak et al[44], 2020	5-lipoxygenase derivatives as serum biomarkers of a successful dietary intervention in patients with non-alcoholic fatty liver disease	68 cases (human study)	Reduction of oxidized omega-6 metabolites serum levels is associated with successful weight reduction and reduced liver steatosis	Reduction in body mass by more than 7% significantly improved steatosis stage, waist circumference, fatty liver index, triglycerides, and cholesterol
Maciejewska et al[41], 2015	Fatty acid changes help to better understand regression of nonalcoholic fatty liver disease	35 Caucasian individuals with steatosis (human study)	With dietary intervention, liver steatosis reduction is associated with changes in fatty acid profiles	EPA and DHA compete with AA and gamma-linolenic acid for cyclooxygenases and lipoxygenases; ameliorate omega 6 oxidation and hence MASLD
Hua et al[42], 2017	Alternation of plasma fatty acids composition and desaturase activities in children with liver steatosis	111 school children (human study)	Children with liver steatosis were highly associated with obesity and insulin resistance	Children with high-grade liver steatosis exhibited higher proportions of dihomo-gamma-linolenic acid (C20: 3n-6), adrenic acid (C22: 4n-6), and docosapentaenoic acid (C22: 5n-6)
Santoro et al[40], 2013	Oxidized metabolites of linoleic acid as biomarkers of liver injury in nonalcoholic steatohepatitis	Review article	The link between oxidative stress and increased production of reactive oxygen species in the liver to oxidation of n-6 polyunsaturated fatty acids and production of specific lipid oxidation metabolites	PNPLA3 plays a role in remodeling TAG in lipid droplets, as they accumulate in response to food intake, and PNPLA3 gene (rs738409) plays its role in the development of fatty liver possibly by interacting with the dietary intake of n-6:n-3 PUFA ratio, dietary intake of n-6:n-3 PUFA ratio
Kaikkonen et al[47], 2021	Associations of serum fatty acid proportions with obesity, insulin resistance, blood pressure, and fatty liver: The cardiovascular risk in young finns study	3596 cases participated in 1980, and follow-up examination carried out 2883 in 2001 (human study)	GLA was positively associated with obesity	The GLA percentage displayed consistent positive outcome association
Mäkelä et al[48], 2022	Associations of serum n-3 and n-6 polyunsaturated fatty acids with prevalence and incidence of non-alcoholic fatty liver disease	2682 males, 920 females (human study)	FLI is a mathematic formula based on BMI, waist circumference, and serum triglyceride and gamma-glutamyl-transferase concentrations for predicting the presence of liver fat	When the n-6 PUFAs were investigated individually, higher LA and AA concentrations were associated with a lower FLI and lower odds for hepatic steatosis, whereas higher GLA and DGLA concentrations were associated with higher FLI
Pertiwi et al[45], 2020	Associations of linoleic acid with markers of glucose metabolism and liver function in South African adults	633 black South Africans (human study)	Dietary and circulating LA were inversely associated with markers of impaired liver function	There is inverse relation between circulating LA and T2D risk
Nagao et al[39], 2005	Dietary conjugated linoleic acid alleviates nonalcoholic fatty liver disease in Zucker (fa/fa) rats	2 groups of male Zucker rats (n = 6) (animal study)	Dietary CLA enhanced fatty acid B-oxidation not only in the liver but also in other tissues in obese rats	CLA alleviates hepatomegaly and triglyceride accumulation in NAFLD rats
Hegazy et al[43], 2019	Diabetes mellitus, nonalcoholic fatty liver disease, and conjugated linoleic acid (omega 6): What is the link?	50 type 2 Egyptian diabetic patients controlled on oral hypoglycemic drugs together with 20 age- and sex-matched healthy participants (human study)	Serum CLA levels were lower in NAFLD patients and associated with insulin resistance and obesity	Low serum CLA levels correlated with advanced NAFLD grades

PUFA: Polyunsaturated fatty acid; MASLD: Metabolic dysfunction-associated steatotic liver disease; NAFLD: Non-alcoholic fatty liver disease; EPA: Eicosapentaenoic acid; DHA: Docosahexaenoic acid; AA: Arachidonic acid; LA: Linoleic acid; GLA: Gamma-linolenic acid; BMI: Body mass index; CLA: Conjugated linoleic acid; T2D: Type 2 diabetes; FLI: Fatty liver index; TAG: Triacylglycerol.